Review Article
Free Access
Sirtuin-dependent epigenetic regulation in the maintenance of genome integrity
Abstract
Sirtuins are a family of deacetylases that target histone and non-histone proteins and require NAD+ as an enzymatic cofactor for their enzymatic activity. This requirement confers sirtuins with the ability to detect changes in metabolism and energy homeostasis and to coordinate cellular responses to maintain genome integrity. Thus, sirtuins are crucial in the crosstalk between environment and genome, and therefore in responses to stress at the cell and organism levels. Sirtuins play a major role in maintaining genome integrity, largely through regulation of epigenetic mechanisms. They target different histone marks, including H4K16Ac, H3K9Ac, H3K56Ac and H3K18Ac, and non-histone components of the chromatin machinery, such as enzymes and structural proteins. Here we summarize our current view on the link between sirtuins and epigenetics, one that reflects the continual adaptation of the genome to stress.
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H4K16Ac deasetylaatio ja H4K20 metylaatiot ja DSB korjaus
Entsyymit PR-SET7, SUV320H1, SUV420H2
SIRT3
SIRT3 lokalisoittuu pääasiassa mitokondriaan, jossa se toimii primäärisenä deasetylaasina. Kuitenkin pieni SIRT3- alapopulaatio sijaitsee tumassa. Tietojen mukaan tämä tumassa oleva SIRT3 toimii histonideasetylaasina (HDAC) substraattispesifyyden suhteen lähinnä SIRT2: ta muistuttavalla tavalla ja (rekrytoituna keinotekoisesti geenille) se on transkriptiota vaimentavaa H4K16Ac:n ja H3K9Ac:n deasetylaatiolla. Mutta SIRT3:n menetys ei korreloi yleiseen H4K16Ac:n ja H3K9Ac:n lisääntymään kuten SIRT1 ja SIRT2 menetyksessä tapahtuu, ja tämä viittaisi siihen, että SIRT3 saattaisi säädellä vain jotain tiettyä geenialaryhmää. Tämän kanssa yhtäpitävästi tumassa olevan SIRT3:n on raportoitu joutuvan stressioloissa nopeasti hajoitukseen, mikä johtaa tiettyjen stressiin liittyvien ja nukleaarisesti koodautuvien mitokondriaalisten geenien ilmenemän modulaatioon.
• SIRT3 is mainly localized in the mitochondria, where it acts as the primary deacetylase. However, a small subpopulation of SIRT3 resides in the nucleus. Data show that this nuclear SIRT3 functions as an HDAC that, in terms of substrate specificity, closely resembles SIRT2 and that is transcriptionally repressive when artificially recruited to a reported gene through deacetylation of H4K16Ac and H3K9Ac 51. Unlike loss of SIRT1 or SIRT2, loss of SIRT3 does not correlate to a global increase in H4K16Ac or H3K9Ac, suggesting that this nuclear SIRT3 might regulate only a specific subset of genes. Consistent with this idea, nuclear SIRT3 has been reported to undergo rapid degradation under stress conditions that results in modulation of the expression of certain stress‐related and nuclear‐encoded mitochondrial genes 52.
SIRT6
Myös SIRT6 kohdentaa histoniin H3K9Ac.
SIRT6-sirtuiinin suorittama H3K9Ac- deasetylaatio on tärkeä telomeerien rakenteen ylläpidossa ja DNA:n kaksoiskatkoksen korjauksessa. Todellakin SIRT6 on pääsirtuiini, joka DNA:n korjaukseen liittyy. SIRT6:n deasetyloiva aktiivisuus H3K9Ac- histonia kohtaan on tarpeen kaksoiskatkosta ympäröivän kromatiinin struktuurin muuttamisiin. Vasteena DNA:n kaksoiskatkokselle SIRT6 assosioituu kromatiiniin ja alentaa H3K9Ac:n pitoisuuksia siten stabiloiden DNA-PKc entsyymien liittymää kromatiiniin ja mahdollistaen korjaustekijöiden liitymisen DNA-vaurioon.
Lisäksi on havaittu SIRT6:n assosioituvan erityisesti telomeereihin ja ilmentävän hyvin spesifistä H3K9Ac- deasetylaasiaktiivisuutta.
SIRT6:n menetys saa aikaan telomeerisiä puutteita kuten kromosomaalisia pääty-pääty-fuusioita ja ennenaikaista ikääntymistä.
Lisäksi SIRT6 osallistuu telomeerien lokalisoimiseen Wernerin oireyhtymän geenin proteiinissa, joka on eräs DNA helikaasi ja osallistuu telomeerin replikoitumiseen S- faasin aikana. Tämä näytön paljous viittaa siihen, että SIRT6 avustaa erikoistunutta kromatiinia propagoitumaan varmistaen asianmukaista telomeerireplikaatiota.
SIRT6:n säätelemä geenin hiljentäminen H3K9Ac-deasetylaatiolla ilmenee kolmessa pääyhteydessä: NF-kB-signaloinnissa, hypoksiassa faktori HIF-1alfan välityksellä ja aineenvaihdunnassa, jossa se näyttää avustavan transformaation aikaista metabolista vaihdetta, joka tunnetaan Warburg-vaikutuksena. https://en.wikipedia.org/wiki/Warburg_effect
• The other sirtuin related to H3K9Ac is SIRT6.
• Deacetylation of H3K9Ac by SIRT6 is important for maintaining telomere structure and for repairing DNA DSBs 19, 36. In fact, SIRT6 is the principal sirtuin associated with DNA repair. Its H3K9Ac deacetylase activity is required for changes in chromatin structure surrounding DSBs. In response to DSBs, SIRT6 associates with chromatin and decreases H3K9Ac levels, thereby stabilizing the association of DNA‐PKcs to chromatin and enabling repair factors to access the DNA lesions 36. Moreover, SIRT6 has been observed to specifically associate with telomeres, exhibiting very specific H3K9Ac deacetylase activity 19.
• Loss of SIRT6 induces telomeric defects such as end‐to‐end chromosomal fusions and premature senescence. Additionally, SIRT6 is also involved in the telomeric localization of Werner syndrome gene protein, a DNA helicase involved in telomeric replication during S phase. This body of evidence suggests that SIRT6 helps propagate specialized chromatin to ensure proper telomeric replication 19. Deacetylation of H3K9Ac by SIRT6 for regulation of gene silencing appears in three main contexts: NF‐κB signaling; hypoxia through the factor HIF‐1α; and metabolism, where it seems to help control the metabolic switch that occurs during transformation, also known as the Warburg effect 65.
jatkuu myöhemmin 19.45, 14.7. 2018 jatkan 15.7. 2018 käännöstä- 17:06.
H3K56Ac
Tämä histonimerkki on tärkeä merkki genomin vakaudesta. H3K56 on ydindomeeni, joka sijoittautuu nukleosomin sisääntulo- ja ulosmenokohtiin. Hiivassa tämä tähde on asetyloituna lähinnä S-faasissa ja sitten käy läpi nopean deasetylaation ennen kuin solut menevät solusyklin G2/M transitiovaiheeseen. Tämä modifikaatio on tärkeä nukleosomin uudelleen koostumiselle DNA-replikaation ja DNA:n korjauksen jälkeen. Tämän osoittaa fakta asetyloitumiseen taipuvaisen lysiinin puutteesta: jos sitä puuttuu, kannat ovat geneettisesti epästabiileja. Erittäin tärkeä kehittyvän hiivan genomiselle vakaudelle on H3K56:n virheetön asetyloituminen.
https://www.youtube.com/watch?v=QTGiipCaNJk
Koska hiivan Sir2p, hst3p ja hst4p on raportoitu pääasiallisiksi H3K56 Ac deasetylaaseiksi niin nisäkkäissä tämä tehtävä on kirjattu SIRT 1-3- ja SIRT6-sirtuiineille. Nisäkkäissä normaaliolosuhteissa H3K56Ac on sijoittautuneena kautta koko tuman, muta DNA-vauriossa sen pitoisuudet nousevat ja se sijoitautuu DNA.n vauriokohtiin, ja niissä se asettuu samaan kuin
γ‐H2AX, pATM, Chk2 ja p53. Kaikki tiedot viitatavat siihen, että asianmukainen H3K56 Ac-säätö on kriittinen genomin vakaudelle ja DNA-vasteelle.
• H3K56Ac: an important mark for genome stability
• H3K56 is a core domain residue that localizes at the entry and the exit points of nucleosomes. In yeast, this residue is acetylated predominantly during S phase, and rapidly undergoes deacetylation when cells enter G2/M 87-93. This modification is important for nucleosome assembly following DNA replication and DNA repair, as evidenced by the fact that strains lacking a lysine amenable to acetylation at this position are genetically unstable 94, 95. All evidence suggests that correct acetylation of H3K56 in budding yeast is paramount for genome stability. Whereas in yeast Sir2p, Hst3p and Hst4p have been reported to be the major H3K56Ac HDACs, in mammals this role has been attributed to SIRT1–3 and SIRT6. 93, 96-100 (Fig. 1). In mammals, under normal conditions H3K56Ac is spread throughout the nucleus, but upon DNA damage its levels increase and it concentrates in the DNA damage foci, where it colocalizes with γ‐H2AX, pATM, Chk2 and p53 100. All data indicate that proper regulation of H3K56Ac is critical for genome stability and DNA response.
H3K56Ac:n deasetyloituminen SIRT6:lla näyttää olevan rajoittunut pitämään yllä H3K56Ac:n dynaamisia pitoisuuksia telomeerien kromatiinissa koko solusyklin ajan (eikä siten kuin SIRT1-3- deasetylaatiosissa). SIRT6 on liitetty myös telomeerien integriteetin ylläpitämiseen H3K56Ac-deasetylaatiolla ( sen lisäksi että SIRT säätelee H3K56Ac:ta), sillä SIRT6 näyttää olevan kriittinen estämässä telomeerien vikatoimintaa ja harhautuneitten kromosomipäätyjen keskeisiä fuusioita.
Tämä histonimerkitsijä säätyy erilaisilla sirtuiineilla, mikä tosiasia painottaa sen säätelyn tärkeyttä genomin suojauksen varmsitamsiessa. Jatkotutkimuksia kuitenkin tarvitaan määrittämään näiden sirtuiinien joko suora ko-operaatio tai toisiaan täydentävyys vasteena eri stimuluksille.
• Unlike deacetylation by SIRT1–3, deacetylation of H3K56Ac by SIRT6 seems to be restricted to maintaining the dynamic changes in H3K56Ac levels in telomeric chromatin throughout the cell cycle 101. Together with regulation of H3K9Ac, deacetylation of H3K56Ac by SIRT6 has also been linked to maintenance of telomere integrity, as it is critical for preventing telomere dysfunction and aberrant chromosomal end‐to‐end fusions 19, 101, 102. The fact that this histone mark is regulated by different sirtuins underscores the importance of its regulation to ensure genome protection. However, further studies on this regulation will be required to determine whether these sirtuins cooperate directly or perform complementary roles in response to different stimuli.
H3K18Ac deasetyaatio. Uusi sirtuiinien transkriptionaalisen vaimennuksen merkitsijä
• Deacetylation of H3K18Ac: a new transcriptional repression mark for sirtuins
SIRT7 on viime aikoina liitetty erään ei tumaperäisten geenien sarjan transkription repressioon niiden promottoreiden H3K18Ac:n deasetylaatiolla.
SIRT7 kohdentaa tuumorisuppressioon liittyvän geeniverkostoon tekemällä interaktion syöpään assosioituvan transkriptiofaktorin ELK4 kanssa. Näissä promoottoreissa tapahtuva SIRT7 tekemä deasetylaatio on välttämätön ihmisen syöpäsolujen essentiellien piirteiden ylläpidolle.- kuten ankkuroitumisesta riippumaton kasvu ja kontakti-inhibition välttö. Edelleen SIRT7 vaaditaan myös H3K18 yleiseen hypoasetylaatioon, mikä liittyy viruksen onkoproteiiniin E1A, joka vastaa solun transformaatiosta. Lisäksi SIRT7 vähentämisen (depleetion) on raportoitu alentavan tumorigenisyyttä ihmissyövän xenografteissa hiiressä. Kaikenkaikkiaan nämä löydöt viittaavat siihen H3K18Ac- deasetylaasiaktiivisuudellansa SIRT7 on tärkeä kromatiinin säätelyssä, solujen transformaatio-ohjemissa ja tuumorin mudostumisessa in vivo, elävässä kehossa.
• SIRT7 has recently been linked to repression of transcription of a set of non‐nucleolar genes, through deacetylation of H3K18Ac at their promoters 103.
• SIRT7 targets a network of genes related to tumor suppression through its interaction with the cancer‐associated transcription factor ELK4. Deacetylation of H3K18Ac by SIRT7 at these promoters is necessary for maintaining essential features of human cancer cells, such as anchorage‐independent growth and escape from contact inhibition. Furthermore, SIRT7 is also required for the global hypoacetylation of H3K18 associated with the viral oncoprotein E1A, which is responsible for cellular transformation. Moreover, depletion of SIRT7 has been reported to reduce the tumorigenicity of human cancer cell xenografts in mice 103. Altogether, these findings suggest that SIRT7, through its H3K18Ac deacetylase activity, is important in chromatin regulation, cellular transformation programs and tumor formation in vivo 103.
SIRT7 lisäksi myös SIRT2 on äskettäin syyllistetty transkriptionaaliseen repressioon H3K18Ac- deasetylaation tekemisestä . Eräässä toisessa Listera monocytogenes-bakteeria koskevassa tutkimuksessa isäntäkehon SIRT2 translokoitui tumaan ja vaimensi erään geenialaryhmän. Tämä prosessi johtui bakteerin pintareseptorista InLB ja bakteerin infektoimiselle sen merkitys on kriittinen. Mielenkiintoinen havainto oli, että infektioituminen oli heikompaa niissä soluissa, joissa SIRT2 aktiivisuus oli estettynä tai Sirt2-/- soluissa.
• In addition to SIRT7, SIRT2 has also recently been imputed in transcriptional repression through H3K18Ac deacetylation. In one study, upon infection of human cells with the bacterium Listeria monocytogenes, the host SIRT2 translocated to the nucleus and repressed a subset of genes. This process depends on the bacterial surface receptor InLB and is critical for bacterial infection. Interestingly, the authors of the study observed that infection was impaired in cells in which SIRT2 activity was blocked and in Sirt2−/− cells 104.
•
Sirtuiinit säätelemässä histoniytimiä H2A ja H2B
Myös histoniytimet H2A ja H2B on tunnistettu sirtuiinien substraatteina.
Esimerkiksi SIRT1 on osallistunut H2A variantin H2A.Z hajoittamiseen. Se liittyy aktiiviin kromatiiniin ja sillä on essentielli osa kehityksen aikana.
Trypanosoma brusei-mikrobisssa on havaittu kaksi sirtuiinia, TbSir2RP1 osoittaa H2A- ja H2B-histonispesifistä ADP-ribosyylitransferaasi- ja deasetylaasiaktiivisuuksia ja oletetaan niiden osallistuvan DNA:n korjaukseen.
Erityisesti SIRT1:n yliesiintymä indusoi NAD+-riippuvalla aktiivisuudellaan H2A.Z:n alassäätymisen.
SIRT1 osallistuu H2AZ deasetylaatioon ja siitä seuraa histonin ubikitinoituminen lysiineihin K15 ja K 121 ja lopulta niiden hajoaminen proteosomisilppuritiessä.
Sydänhypertrofiatiloissa tämä mekanismi indusoi solukasvua ja inhiboi apoptoosia.
Tähän löytöön johdonmukainen viimemaikainen työ on osoittanut prostatasyöpäsoluissa histonin H2A olevan ylössäätyneenä ja SIRT1-sirtuiinin olevan alassäätyneenä ja H2A.ZAc on osallistunut onkogeenin ylössäätymiseen. Nämä löydöt viitatavat SIRT1.n mahdollisuuten toimia terapeuttisen kohdemolekyylinä prostatasyövässä.
• Sirtuins in regulation of the core histones H2A and H2B
• Among core histones, H2A and H2B have also been identified as sirtuin substrates (Fig. 1). For instance, SIRT1 has been implicated in degradation of the H2A variant H2A.Z, which is associated with active chromatin and plays an essential role in development. Interestingly, one of the two sirtuins present in Trypanosoma brucei, TbSir2RP1, shows H2A‐ and H2B‐specific ADP‐ribosyltransferase and deacetylase activities, which have been proposed as being involved in DNA repair 105. Overexpression of SIRT1 specifically induced downregulation of H2A.Z via NAD+‐dependent activity. SIRT1 is involved in deacetylation of H2AZ, which results in ubiquitination of the histone at Lys115 and Lys121 and, ultimately, in its degradation via a proteasome‐dependent pathway. Under cardiac hypertrophy conditions, this mechanism induces cell growth and inhibits apoptosis 106. Consistent with this finding, recent work has shown that in prostate cancer cells histone H2A and SIRT1 are upregulated and downregulated, respectively, and that H2A.ZAc is implicated in oncogene upregulation 107. These findings suggest the potential of SIRT1 as a therapeutic target for prostate cancer 107.
•
Histoni H1 , linkkihistoni kromatiinisäätelyssä
• H1: a linker histone for chromatin regulation
Toinen tärkeä funktionaalinen suhde sirtuiinien ja histonien kesken käsittää linkkihistonin H1 ja on erityisesti relevanttia fakultatiivisen heterokromatiinin säätelylle.
Tutkijat ovat tehneet oletuksen, että H1-asetylaatio(N-terminaaliseen domeeniin) saattaisi vaikuttaa intra- ja internukleosomaalisia vuorovaikutuksia, jotka suosivat vähemmän tiukkaa kromatiinirakennetta –samaan tapaan kuin sirtuiinin ja histoniytimien välinen vaikutus. Tässä mielessä näyttö viittaa siihen, että SIRT1 rekrytoi histonia H1, tekee interaktion sen kanssa ja deasetyloi lysiiniin K26. Mielenkiintoista on myös äskettäin kuvattu SIRT1:n , histonin H1 isoformin H1.5 ja vaimennuksen merkitsijän H3K9me2:n genominlaajuinen samaan sijoittautuminen, mikä oletetaan vaadittavan erilaistuneiden imettäväissolujen geeni-ilmenemän ylläpitoon. Toinen mielenkiintoinen linkki, joka punoo SIRT1:n ja H1:n erilaistumiseen ja kehitykseen: SIRT1 on kuvattu osana PRC4-kompleksia, jossa on H3K27me3-histonitansferaasin nopeuttajaa (EZH2) ja joka on fundamentaalinen erilaistumsiesas. PRC4:n yhteydessä EZH2 on osoittanut metyloivan pikemminkin H1K26-histonin kuin H3K27:n. Sen mukaan SIRT 1 yhdessä EZH2:n kanssa on vaikuttanut H1K26 deasetylaation ja mahdollistanut tämän lysiinitähteen metylaation. Kiinnostavaa, että heterokromatiiniproteiini HP1 tunnistaa H1K26me2 ja vaikuttaa osaltaan fakultatiivisen heterokromatiinin (FH) säätelyyn, mikä taas saattaisi osaltaan vaikuttaa geeninilmenemismallin tiukempaan, spesifisempään kontrolliin solujen erilaistumisen ja transformoitumisen aikana.
• Another important functional relationship between sirtuins and histones involves the linker histone H1 and is particularly relevant for the regulation of FH. Researchers have hypothesized that acetylation of H1 (at its N‐terminal domain) might affect intra‐ and inter‐nucleosomal interactions to favor a less compact chromatin structure, similarly to the interplay between sirtuins and core histones 28. In this sense, evidence suggests that SIRT1 recruits, and interacts with, histone H1, and deacetylates it at lysine K26 28. Interestingly, an important genome‐wide colocalization of SIRT1, the histone H1 isoform H1.5 and the repressive mark H3K9me2 has recently been described and has been suggested as being required for the maintenance of gene expression in differentiated mammalian cells 108. Another interesting link tying SIRT1 and H1 to differentiation and development is that SIRT1 has been described as part of polycomb repressive complex 4 (PRC4), a complex that contains the H3K27me3 histone methyltransferase enhancer of zeste homolog 2 (EZH2) and is fundamental in differentiation 109. In the context of PRC4, EZH2 has been shown to specifically methylate H1K26 rather than H3K27.
• Accordingly, researchers have suggested that SIRT1, in concert with EZH2, deacetylates H1K26 to enable methylation of this residue. Interestingly, heterochromatin protein 1 (HP1) recognizes H1K26me2 and contributes to FH regulation, which might contribute to tighter, more specific control of gene expression patterns during cell differentiation and transformation 110, 111.
Liästutkimukset ovat osoittaneet, että mitoosissa SIRT1 asettuu kromatiiniin prometafaasista telofaasiin ja antaa osansa yleiseen kromosomaaliseen tiivistymiseen histonideasetylaatiolla ja linkki-histonin H1 kromatiinikuormaukseen ja kondensiini-I kompleksiin, mikä vaikuttaa osaltaan kromosomin integriteettiä ja stabiliteettia. Ei tiedetä, onko osallisena H1K26-deasetylaatio.
• Additional studies have demonstrated that during mitosis SIRT1 localizes to chromatin from prometaphase to telophase, and that it contributes to global chromosomal condensation via histone deacetylation and chromatin loading of the linker histone H1 and the condensin I complex, thereby contributing to chromosome integrity and stability 112. However, whether deacetylation of H1K26 is involved is unknown.
C-elegans -tutkimuksissa synergia SIRT1 ortologin SIR2.1 ja linkkihistonin HIS-24(H1.1) välillä on essentielli pitämässä yllä itusolulinjan merkitsijää H3K27me3. SIR1.1 deasetyloi H3K9Ac subtelomeerisissä alueissa, mikä on edellytys H3K27:n metylaatiolle. HIS-24 tekee spesifisen interaktion H3K27:n kanssa osana heterokromatiinin ylläpitomekanismia.
• In Caenorhabditis elegans the synergy between the SIRT1 ortholog SIR2.1 and the linker histone HIS‐24 (H1.1) is essential for maintaining the mark H3K27me3 in the germ line. SIR2.1 deacetylates H3K9Ac at subtelomeric regions as a prerequisite for H3K27 methylation. Subsequently, HIS‐24 specifically interacts with the H3K27 region as part of a mechanism of heterochromatin maintenance 113. Sirtuiinit ja epigeneettinen mekanismi
Kuten yllä mainittiin sirtuiinit ovat evoloituneet säätelemään kromatiinidynamiikan ja epigeneettisen säätelyn pääentsyymeitä varmistaen genomin suojelun. Kuitenkin sirtuiinit ovat myös hyvin olennaisesti linkkiytyneet ei-entsymaattisiin epigeneettisen koneiston komponenteihin. Tässä kappaleessa pohditaan sirtuiinien interaktioita sekä entsymaattisten että ei entsymaattisten komponenttien kanssa. • Sirtuins and epigenetic machinery As we mentioned above, sirtuins have evolved to regulate major enzymes involved in chromatin dynamics and epigenetic regulation to ensure genome protection. However, sirtuins are also intricately linked to non‐enzymatic components of epigenetic machinery. In this section, we discuss interaction of sirtuins with enzymatic as well as non‐enzymatic components (Fig. 2).
Figure 2
Open in figure viewerPowerPoint
Sirtuins regulate chromatin machinery function. Sirtuins regulate genome stability in part through modulation of specific chromatin‐associated factors and in the context of a wide variety of processes. The cartoon summarizes known interplays between sirtuins and some of these factors in non‐stressed (left part of the cartoon) or stressed conditions (right part of the cartoon, in brown background). SUV39H1: an important methyltransferase in heterochromatin regulated by SIRT1 SUV39H1 was the first lysine methyltransferase ever described.
It is highly specific for H3K9me3; in fact, it is the most important
H3K9me3 methyltransferase in mammals (114) .
It contributes to chromatin organization by maintaining
H3K9me3 in both pericentromeric and telomeric CH (111, 115). Loss of
both SUV39H1 and its close variant SUV39H2 in mice results in complete
loss of H3K9me3 in pericentromeric heterochromatin as well as reduced
H3K9me3 levels in telomeres ( 115).
Importantly, this loss involves delocalization of HP1 and relocalization
of H4K16Ac to heterochromatic foci, which result in diminished
heterochromatin levels (27).
Consequently, mice lacking both enzymes exhibit compromised chromatin segregation, delayed G2/M transition and damaged DNA 27.
As we mentioned earlier, SIRT1 promotes formation of FH by
coordinating several events together with other enzymes.
For instance,
through its functional relationship with SUV39H1, it promotes spreading
of the repressive mark H3K9me3. First, SIRT1 deacetylates H3K9Ac to enable methylation of this residue by SUV39H1. Moreover, SIRT1 directly recruits SUV39H1 to specific regulatory regions.
This interaction involves the N‐terminal domain of SIRT1 (which is also
involved in recruitment of H1 )(28) and the first 88 residues of
SUV39H1, which encompass the HP1 binding region (residues 1–44) and the chromodomain
(residues 44–88) (Fig. 2).
Furthermore, SIRT1 deacetylates
SUV39H1 at residue K266 in its catalytic SET domain, rendering the
enzyme more active. K266 has been conserved over evolution in eukaryotic
SUV39H1 orthologs as well as in numerous SET‐containing
methyltransferases. Although the function of K266 remains unknown,
structural studies suggest that it is located in an exposed loop of the
SET domain that is important for proper folding of the enzyme 116. Thus,
SIRT1 interacts with, recruits and deacetylates SUV39H1, thereby making
it more active. This increase in SUV39H1 activity in turn leads to
augmented levels of H3K9me3.
Consequently, loss of SIRT1 strongly affects SUV39H1‐dependent
H3K9me3 levels, thereby promoting delocalization of HP1.
An important example of cooperation between SIRT1 and SUV39H1 in FH
regulation occurs in the protein complex eNoSC, which senses energy
status and controls nucleolar rRNA transcription. eNoSC contains SIRT1,
SUV39H1 and the H3K9me2‐binding protein nucleomethylin and
is responsible for silencing the rDNA locus by controlling ribosome
biosynthesis under nutrient or energy deficiency (117). Regulation of
the rDNA locus is crucial, as its highly repetitive nature is prone to
homologous recombination events which lead to damaging chromosomal
rearrangements. Accordingly, this complex provides a regulatory link between cellular energy balance and the epigenetic state of the rDNA locus (117). The interplay between SIRT1 and SUV39H1 extends beyond regulation of FH. Among sirtuins, SIRT1 is probably the one that is most involved in maintaining CH in pericentromeric heterochromatin as well as telomeric
regions, despite the fact that it is either absent or present at very
low levels in pericentromeric heterochromatin foci (27).
Interestingly,
approximately 50% of Sirt1−/− MEFs exhibit diminished levels of H3K9me3
in the CH foci, a trend that correlates with mislocalization of HP1α
(27) and derepression of the heterochromatinized γ‐satellite (33).
Accordingly, SIRT1 transfection in
these cells recovers the levels of H3K9me3 in the pericentric foci
(27).
All the published data suggest that the strongest link
between SIRT1 and CH probably results from the functional relationship
of the former with SUV39H1. In fact, SUV39H1 has been shown to participate in cellular response to oxidative stress through a SIRT1‐dependent mechanism: in the chromodomain, SIRT1 inhibits polyubiquitination of SUV39H1 by the E3 ubiquitin ligase MDM2, thereby preventing its subsequent proteasomic degradation and increasing the stability
of SUV39H1 by nearly four times (Fig. 2). In vivo, this increase in
SUV39H1 levels accelerates turnover of SUV39H1 in pericentromeric
heterochromatin regions, which contributes to genome protection.
Thus, in vivo, oxidative and metabolic stress
conditions that lead to SIRT1 upregulation cause a SIRT1‐dependent
increase in SUV39H1 levels – a finding that suggests a direct link
between stress response and SUV39H1 dynamics in heterochromatin
structure as a mechanism of genome stability (33). The finding of a close functional relationship between SIRT1 and SUV39H1
suggested a more intimate regulation between these groups of enzymes
than previously understood. Indeed, since its
discovery, other functional relationships between enzymes of these
classes have been described and extensively studied.
SIRT2 kontrolloi histonimarkkeria H4K201 solusyklin aikana säätelemällä PR-SET7.
https://www.genecards.org/Search/Keyword?queryString=PR-SET7 . KMT5A. N-lysine Methyltrasnferase KMT5A. SIRT2 controls the histone mark H4K20me1 during the cell cycle by regulating PR‐SET7
Another major functional relationship between a histone deacetylase and a methyltransferases is that between SIRT2 and PR‐SET7, for regulating cell cycle progression. As we mentioned earlier, SIRT2 is crucial for regulating H4K16Ac throughout the cell cycle and for establishing PR‐SET7‐mediated H4K20me1 during early mitosis. H4K20me1 is established by PR‐SET7 in late G2/early M and is critical for metaphasic chromosome compaction during mitosis and mitotic exit (83, 118)as well as in DNA repair and replication (119-121). During late M/early G1, H4K20me1 is subsequently methylated into H4K20me2 (by SUV420H1) or H4K20me3 (by SUV420H2), which are required for DNA repair or for heterochromatin structure formation, respectively (79-81).
Evidence suggests that during mitosis SIRT2 regulates H4K20me1 deposition via PR‐SET7 and promotes the spread of H4K20me1. The proposed model involves several steps, beginning with the arrival of PR‐SET7 to specific chromatin regions during late G2, where it recruits SIRT2 during G2/M. In turn, SIRT2 promotes the enzymatic activity of PR‐SET7 through its deacetylation at K90 and the deacetylation of H4K16Ac from the neighboring nucleosome. Deacetylation of PR‐SET7 induces its mobilization and SIRT2‐bound PR‐SET7 monomethylates H4K20 in the adjacent nucleosome. This occurs successively and enables the spread of PR‐SET7 binding to chromatin as well as subsequent H4K20me1 deposition( 31) (Fig. 2). Interestingly, a very recent paper suggests that PR‐SET7 might in turn control H4K16Ac (as well as H4K20me3) to regulate the pausing dynamics of RNA polymerase II (Pol II) (122).
Interestingly, under stress during G2/M, the interaction between SIRT2 and PR‐SET7 increases significantly, as do global H4K20me1 levels, suggesting a previously unknown G2/M checkpoint mechanism. This would be the first link between H4K20me1 and a cell cycle checkpoint, and between H4K20me1 and SIRT2‐dependent stress response. These findings corroborate a dynamic role for sirtuins in controlling the cell cycle through modulation of epigenetic regulatory information.
EZH2: a possible target for sirtuin activity in development and differentiation The histone methyltransferase EZH2 is a polycomb group protein that, together with others, forms the multi‐subunit PRC2. Its primary function is to deposit the histone mark H3K27me3 to promote transcriptional repression. However, researchers have suggested that it also facilitates DNA methylation by recruiting DNA methyltransferases ( 123, 124). As we mentioned above, EZH2 and SIRT1, together with other polycomb group proteins, form part of PRC4, which is involved in chromatin regulation during cellular differentiation 125. Although there is no evidence that EZH2 is a substrate of SIRT1, it does contain the conserved catalytic SET domain and K266, the residue deacetylated by SIRT1 in SUV39H1, which suggests that the enzyme is possibly involved in regulating acetylation/deacetylation (27). However, further studies are required to determine whether such a role exists. To date, only one study has proposed that depletion of SIRT1 increases EZH2 protein stability, which in turn enhances the ability of EZH2 to repress expression of target genes( 126).
The relationship between SIRT1 and EZH2 is evidence of the significance of the latter in cell differentiation.
In fact, among sirtuins, SIRT1 and SIRT7 are the only ones that seem to be crucial for development and cell differentiation, as demonstrated by the fact that only approximately 50% of SIRT1 or SIRT7 knockout (KO) mice reach birth (127-134). Furthermore, SIRT1 levels also decrease during ES cell differentiation (125).
Interestingly,(SIRT1 has been implicated in proliferation and differentiation of neural stem cells (NSCs) and neurodegenerative diseases 135-138. SIRT1 inhibition can promote neural differentiation of human embryonic stem cells and attenuates the heat shock response (138, 139). Researchers recently reported that, during differentiation of pluripotent stem cells (iPSCs) into NSCs, SIRT1 levels decrease and microRNA‐34a (miR‐34a) levels increase. Moreover, there is evidence suggesting that this differentiation might be inhibited by SIRT1 and regulated by miR‐34a 140.
Sirtuins and regulation of histone acetyltransferases
SIRT1 antagonisti on histoniasetylaasi HAT p300.
Interestingly, sirtuins target enzymes that cooperate with them in chromatin regulation as well as antagonistic enzymes such as HATs. Such interactions probably contribute to efficient fine‐tuning of cellular response on demand (e.g. under stress) to ensure genome protection. For example, sirtuins regulate the HAT p300, a major co‐transcriptional activator that is expressed ubiquitously and required for cellular processes such as growth, differentiation and survival (141, 142). In addition to its HAT activity, p300 also acetylates itself and various non‐histone proteins, including p53, c‐myc, HMG proteins and nuclear receptors (142-145). p300 autoacetylation induces a conformational change that is critical for the transition between chromatin modification and VP16‐mediated assembly of the pre‐initiation complex (146). In this sense, tight control of p300 function is critical for ensuring regulation of these pathways and for maintaining heterochromatin structure. Studies have shown that SIRT1 interacts with and represses p300 transactivation, and that this repression requires the NAD+‐dependent deacetylase activity of SIRT1, which deacetylates residues K1020 and K1024 of the CRD1 transcriptional repression domain of p300. Given the importance of p300 as limiting transcriptional cofactor, its deacetylation and repression by SIRT1 could be crucial for regulation of various pathways during metabolism and cellular differentiation (53). Sirtuiineista vain SIRT2 pystyy deasetyloimaan autoasetyloituneen HAT proteiinin. In contrast, some in vitro studies have indicated that SIRT2 is the only sirtuin that can deacetylate autoacetylated p300 54. Furthermore, in one study on cells, RNAi‐mediated depletion, or chemical inhibition, of SIRT2 increased Ac‐p300 levels and induced activation of a gene reporter (54). Despite these seemingly contradictory results, the full body of evidence suggests that p300 undergoes a dynamic cycle of acetylation and deacetylation that tightly regulates its activity (Fig. 2).
HAT perheen proteiineja on alaperhe MYSTdomain ( Znf C2H2_ HAT) ja siihen kuuluvat MOF ja TIP60. Ne ovat SIRT1 substraatteja.
. Interestingly, sirtuins have also been linked to regulation of the MYST family of HATs. Currently, two MYSTs are known to be SIRT1 substrates: MOF and TIP60 (Fig. 2). MOF plays a critical role in transcription activation and is the main H4K16Ac HAT in mammals (147, 148). The human ortholog of MOF (hMOF) acetylates itself in the conserved MYST domain (C2HC zinc finger and HAT) in vitro and in vivo. SIRT1 has been found to interact with and deacetylate this domain (55). This deacetylation might help MOF bind to chromatin, as reflected in the finding that non‐acetylated hMOF strongly binds to nucleosomes, whereas acetylated hMOF exhibits weakened binding. Consistent with these findings, recruitment of hMOF to chromatin increases upon SIRT1 overexpression and decreases after SIRT1 knockdown. Thus, depletion of SIRT1 diminishes recruitment of hMOF to the target gene
HoxA9 ja SIRT1 HoxA9, which in turn has been associated with a decrease in levels of H4K16Ac and with repressed transcription of HoxA9 (55). In contrast, it has been described that, in adult hematopoietic stem and progenitor cells, SIRT1 binds to HoxA9 gene, deacetylates H4K16 and promotes polycomb‐specific repressive histone modifications (149). TIP60 ja SIRT1 UV-säteily. Evidence suggests a dual role of SIRT1 function in gene expression through H4K16 regulation, depending on cell type or cellular conditions, and an important dynamic interplay between SIRT1 and hMOF in the complex regulation of H4K16 acetylation.
TIP60 is the other MYST targeted by SIRT1. It acetylates many substrates, including histones and p53, to promote apoptosis following UV irradiation. TIP60 acetylates itself (primarily in response to DNA damage), which is paramount for its activation, and acetylates the DNA‐damage‐specific variant of histone H2A (H2AX) in a process required for DNA damage response. Additionally, SIRT1 has been identified as a physical interaction partner of TIP60 and data show that SIRT1 specifically deacetylates TIP60 in response to DNA damage and stimulates its proteasome‐dependent degradation in vivo (56, 57). SIRT1 depletio. Furthermore, depletion of SIRT1 by RNAi causes hyperacetylation of H2AX and enhances accumulation of MDC1, breast cancer 1 and Rad51 foci in nuclei. Accordingly, a role for SIRT1 in DSB signaling, involving hMOF and TIP60, has also been described in a more recent study (37).
In the absence of stress, SIRT1 binds to and deacetylates the enzymatic domains of hMOF and TIP60, inhibiting their respective activities and promoting their ubiquitination‐dependent degradation.
However, DNA damage results in decreased binding of SIRT1 to hMOF or TIP60, which in turn results in hyperacetylation of each MYST family member and to activation of DNA damage signaling (37, 150, 151). Within 4 h after damage, SIRT1 reassociates with both MYST members, restoring their deacetylated states and therefore preventing excessive apoptosis (37). SIRT1–hMOF/TIP60 interaction and hMOF/TIP60 acetylation status seems to be highly controlled by DNA damage signals to maintain critical levels of active hMOF and TIP60 during repair. Altogether, these findings suggest that SIRT1 might repress excessive DNA damage response by repressing hMOF and TIP60 function (37, 56, 57). SIRT1 and SIRT6 in a PARP1 functional relationship. Poly(ADP‐ribose)polymerase 1 (PARP1), the prototype member of the PARP superfamily, is ubiquitously expressed and is responsible for most poly(ADP)ribosylation of proteins in vivo (152). In fact, poly(ADP)ribosylation of histones and other nuclear proteins by PARP1 is among the most important mechanisms that control chromatin structure and integrity in response to DNA damage (152). Some researchers have proposed that poly(ADP)ribosylation might be critical for epigenetic regulation of chromatin dynamics (153-158). PARP1 and its relative PARP2 are important for maintaining the integrity of CH and FH. Both proteins localize to telomeres, centromeres and rDNA, where they interact with and regulate specific partners (159-165).
Sirtuins and PARPs are among the most effective NAD+‐consuming enzymes. Unsurprisingly, some studies have unveiled functional interplay between members of these two families. To study the coordinated functions of SIRT1 and PARP1 in CH, researchers have generated animal and cellular models lacking the corresponding genes (Sirt1 and Parp1). In mice, depletion of both genes results in increased late post‐lethality caused by increased genome instability, suggesting an important role for these proteins in maintaining genome integrity during development (166). In contrast, knockdown of Parp1 in Sirt1−/− mice reverses the chromatin abnormality phenotype associated with loss of SIRT1. According to the authors of the study, this finding suggests an important role for both proteins in subtle regulation of chromatin structure and function. Nevertheless, further work will be required in order to elucidate the functional link between the two proteins and to clarify their respective activities in heterochromatin regulation. Interestingly, under stress, SIRT1 promotes cell survival by deacetylating PARP1 (58) (Fig. 2). In fact, SIRT1‐dependent deacetylation blocks PARP1 activity and protects cells from PARP1‐mediated death 58. Moreover, SIRT1‐deficient cells exhibit increased DNA damage induced PARP1 activity and increased apoptosis inducing factor mediated cell death (167). Some evidence corroborates a possible functional link between these two NAD+‐dependent enzymes in cellular response to DNA damage and in maintenance of genome integrity. However, this is another area that must be clarified in future work. SIRT6 ja PARP1. SIRT6 is the other sirtuin linked to PARP1 activity and is the sirtuin that is most involved in single‐strand break and DSB DNA repair mechanisms. Interestingly, SIRT6 deficient mice exhibit genome instability (168, 169). Under oxidative stress, SIRT6 is recruited to DNA damage sites, where it stimulates repair by directly interacting with and ADP‐ribosylating PARP1 (at Lys521), which is involved in base excision repair (BER) and DSB signaling (38-43) (Fig. 2). DNMT proiteiinit metyloivat DNA:ta. Co-repressorit
SIRT1 and DNA methylation
DNA methyltransferases (DNMTs) add methyl groups to the 5′‐position of cytosine residues of CpG dinucleotides. Methylation of CpG islands leads to recruitment of repressor complexes and to decreased binding of transcription factors(170, 171). Accordingly, actively transcribed DNA is typically hypomethylated, whereas silenced DNA is typically hypermethylated. Mammalian genomes contain three DNMT proteins: DNMT3a and DNMT3b, which are responsible for de novo methylation and modify unmethylated DNA; and DNMT1, which is responsible for maintaining methylation patterns (172-174).
DNMT1 was the first DNMT identified and is the most abundant and ubiquitous one (175-177) . It is crucial for silencing tumor suppressor genes and for cell survival (178). In addition to methylating DNA, DNMT1 also represses transcription via mechanisms such as recruiting transcription corepressor DNMT1‐associated protein 1, HDAC1, HDAC2 and methyl‐CpG‐binding protein to DNA (179-181).
Accordingly, SIRT1 and histone deacetylation activity have been linked to methylation of DNA by DNMT1 at numerous genomic loci, such as nucleolar rDNA and certain tumor suppressor genes(182, 183). In this sense, SIRT1 localizes to promoters of several aberrantly silenced tumor suppressor genes in which 5′ CpG islands are hypermethylated, but not to these same promoters in cell lines in which the genes are expressed and the promoters are not hypermethylated (182). Moreover, human cells with DNMT1 depletion exhibit a loss of DNA methylation and increased levels of H4K16Ac at rRNA genes. DNMT1 interacts with SIRT1 and then recruits it to rRNA genes, suggesting that the former is critical for maintenance of nucleolar structure (183). More recently, studies have demonstrated that post‐translational modification (PTM) (e.g. acetylation, sumoylation, phosphorylation, methylation and ubiquitination) of DNMT1 might correlate to changes in its catalytic activity, DNA binding activity and stability (184-189). Interestingly, 12 lysines in its N‐ and C‐terminal regions are acetylated, and the deacetylation enzyme has been identified as SIRT1 both in vivo and in vitro (20). Furthermore, acetylation/deacetylation of DNMT1 alters its enzymatic activity, its capacity to silence tumor suppressor genes and its ability to regulate the cell cycle (20).
DNMT1 and DNMT3B form part of a silencing complex that also includes members of PRC4, EZH2 and SIRT1 190. The complex forms under oxidative stress, subsequently translocating from non‐GC‐rich to GC‐rich areas. Interestingly, in an in vivo model of colitis, it was found to be similarly enriched at gene promoters (190). The authors of that study affirm that such enrichment might explain the cancer‐specific aberrant DNA methylation and transcriptional silencing that they observed in their model. Altogether, these findings reflect the significant functional relationship between DNMTs and sirtuins.
Crosstalk between SIRT6 as histone modifier and SNF2H as chromatin remodeler Cells have developed multiple mechanisms to protect and repair DNA. Because eukaryotic DNA is packaged within nucleosomes, it presents an additional physical barrier that DNA repair factors must traverse in order to access damage sites. Therefore, chromatin remodelers are vital for DNA repair: they are recruited to damage sites, where they structurally decondense chromatin to enable repair (191). Researchers have proposed that the ATP‐dependent chromatin remodeler SNF2H, a member of the imitation switch (ISWI) family, is recruited (downstream of the ubiquitin ligase RNF20) to DNA damage sites (192-195).
SIRT6 has recently been reported to serve as a scaffold protein in DNA damage repair (44). Among factors recruited to DSBs, SIRT6 is one of the first to arrive. Upon arrival, v (to decondense chromatin) and deacetylates H3K56Ac – two crucial steps for proper recruitment of downstream DNA repair factors (Fig. 2). Depletion of SIRT6 and SNF2H leads to defective chromatin remodeling (which in turn causes heightened sensitivity to genotoxic damage) and impaired recruitment of downstream factors such as 53BP1 and breast cancer 1. Notably, SIRT6‐deficient mice exhibit a DNA damage phenotype as well as low levels of chromatin‐associated SNF2H in specific tissue types 44. These results suggest that SIRT6, as a specific scaffold factor, is critical for recruitment of a chromatin remodeler to DNA damage sites and that SIRT6 and SNF2H collaborate in an early and rate‐limiting step of DNA damage repair. HR, DSB damage repair. Furthermore, SIRT1 has been implicated in homologous recombination, a DSB repair pathway, through its interaction with and deacetylation of Werner syndrome gene protein helicase, a member of the RecQ family (45-49). SIRT7 and rDNA regulation. SIRT7 is primarily a deacetylase and is localized to the nucleolus and the nucleus. In the former, it regulates ribosomal DNA gene expression by activating Pol I, although its specific target is unknown (196). Along these lines, researchers have reported that depletion of SIRT7 leads to decreased association of Pol I with rDNA, which in turn causes reduced transcription of Pol I (196). Furthermore, mass spectrometry studies have confirmed that SIRT7 forms part of a complex that also contains the chromatin remodeling complex B‐WICH, UBF and Pol I, and suggest that SIRT7 facilitates transcription of rDNA by interacting with B‐WICH (197). Given that rRNA transcription levels are altered under certain types of stress (e.g. genotoxic stress or calorie restriction), the function of SIRT7 as a stress sensor could be critical for nucleolar regulation. Furthermore, SIRT7 is phosphorylated during mitosis, when it localizes with chromosomes until telophase, at which point it is dephosphorylated and becomes activated for proper rDNA re‐expression after mitosis. Interestingly, SIRT1 can repress transcription of RNA Pol I by deacetylating its component TAFI68 (196). Sirtuins and non‐coding RNA.
MicroRNAs (miRNAs) are small non‐coding RNAs that regulate gene expression. They were first identified in C. elegans as regulators of development (198, 199). They were later reported to inhibit expression of target proteins by three mechanisms: post‐transcriptional repression (through a specific complementarity sequence comprising the first 6–8 nucleotides of the miRNA and the 3′UTR regions of the target gene); destabilization of mRNA; and suppression of translation (200-203). Interestingly, a single miRNA can regulate multiple genes and many genes have several potential miRNA binding sites in their 3′UTR region. Furthermore, some miRNAs can regulate a target gene positively or negatively. In addition, studies suggest that miRNAs might also target the coding regions of genes (204-206). Given such complexity, the effects of a single miRNA are difficult to identify. Expression of most sirtuins (SIRT1, SIRT2, SIRT6 and SIRT7) is regulated by miRNA. It involves multiple miRNAs and results in regulation of different pathways (see Table 1). Among the most important relationships between sirtuins and miRNAs is the one between SIRT1 and miR‐34a, a tumor suppressor gene. miR‐34a forms part of the miR‐34 family, which is involved in cell cycle progression, cellular senescence and apoptosis; however, all of the targets of miR‐34 have not yet been identified (207-213). The miR‐34 family is transcriptionally activated by p53, one of the proteins that are most involved in cancer. Data suggest that miR‐34a inhibits expression of SIRT1 through an miR‐34a binding site within the 3′UTR of SIRT1 (213, 214). Inhibition of SIRT1 by miR‐34a results in increased acetylation of p53 and expression of p21 and PUMA, targets of p53 transcription that are involved in the cell cycle and in apoptosis, respectively. Because miR‐34a itself is a transcriptional target of p53, data corroborate a positive feedback loop in which p53 induces expression of miR‐34a, which in turn suppresses SIRT1. Thus, miR‐34a functions as a tumor suppressor, in part, through a SIRT1–p53 pathway (213, 214). Furthermore, miR‐34a has also been implicated in cell differentiation (215-218). In particular, miR‐34a is involved in differentiation of mouse NSCs; in one study, overexpression of miR‐34a increased the amount of post‐mitotic neurons and led to greater neurite elongation, whereas an miR‐34a antisense had the opposite effect. Interestingly, some data suggest that SIRT1 can mediate this miR‐34a effect on neurite elongation; accordingly, researchers have proposed a molecular mechanism for proper neural differentiation that involves miR‐34a, SIRT1 and p53 (137). In fact, there have been numerous studies on the functional relationship between miR‐34a and SIRT1 that encompass multiple pathways and diseases and that reflect on the importance of said regulatory mechanism.
Table 1. Interplay between sirtuins and miRNAs. The table summarizes our current knowledge about the regulation of sirtuins by miRNA and the functional implications of this regulation. Because of space limitations, the interplay between sirtuins and these miRNAs are not discussed in the main text. However, the references included in the table may help to clarify the important role of this functional relationship between sirtuins and miRNAs. Sirtuin miRNA Related function Reference ' SIRT1 miR‐9
m ESC differentiation (223)
miR‐22 Cellular senescence; stress response; heart failure (223-226) miR‐34a Apoptosis; aging; cell differentiation; senescence; inflammation and metabolism disorders (137, 213, 227-231). miR‐93 Aging (227). miR‐126 Osteosarcoma cell proliferation (232). miR‐132 Stress response (233). miR‐135a ND (223). miR‐138 Mammalian axon regeneration (234). miR‐140 Nutritional cues response (235). miR‐142
Neurodegenerative disorders (236), (237). miR‐181a
Hepatic insulin sensitivity (238). miR‐195
Apoptosis; tissue damage (239, 240). miR‐199a
Hypoxia; cytomegalovirus infection, CMV (241, 242). miR‐199b
ND (223) miR‐200a Epithelial to mesenchymal transition regulation ( 243). miR‐204
Epithelial to mesenchymal transition regulation, EMT (244). miR‐217
Senescence; metabolism; viral infection; angiogenesis (245-248). miR‐373
Cancer cell metastasis(249). miR‐449a
Apoptosis (250). miR‐520 Cancer cell metastasis( 249)
SIRT2
miR‐21 Glioma cell growth (251). SIRT6 miR‐33a/b
Fatty acid metabolism and insulin signaling (252). miR‐34a
Cell differentiation (219) miR‐766
Cell reprogramming (253) SIRT7 miR125a–5p
Human hepatocellular carcinoma (HCC) (254 ) miR‐125b
Human hepatocellular carcinoma; bladder cancer (254, 255)
SIRT6 is the other sirtuin regulated by miR‐34a. Data suggest that miR‐34a is importan
t in the squamous cell differentiation network and that SIRT6 is a critical target in this
context ( 219). Expression of miR‐34a increases with keratinocyte differentiation, whereas
it is suppressed in skin and oral squamous cell carcinoma, squamous cell carcinoma cell
lines and aberrantly differentiating primary human keratinocytes. In this regard, SIRT6
is oppositely expressed to miR‐34a in normal keratinocytes and keratinocyte‐derived tumors ( 219). Näkymiä, Perspectives
Katsauksen löydökset painottavat sirtuiinien tärkeyttä genomin integriteetin ylläpidossa
kompromittoituneissa tilanteissa kuten stressissä ja yleisemmin ottaen tukevat käsitystä
sirtuiinien relevanttisuudesta ikääntymisessä ja useissa ihmistaudeissa, Näille
sirtuiineihin liittyneille funktioille on perustavaa epigeneettisen muistin säätely.
Kuitenkin täsmällisen yleiskäsityksen hankkimiseksi sirtuiinien epigenetiikasta vaaditaan
kyllä sirtuiiniperheenjäsenten keskeisten vaikutusten ja toistensa kattavuuden asteen selkeää
vahvistamista. Sirtuiineilla on yhteisiä kohteita, mikä viitaa siihen, että ne tekevät
yhteistyötä tai täydentävät toisiaan eri stimulusten mukaisesti.
• The findings that we have reviewed here underscore the importance of sirtuins in maintenance of genome integrity under compromising situations such as stress and support the view that, by extension, sirtuins must be relevant in aging and several human pathologies. Regulation of epigenetic memory is fundamental for these sirtuin‐associated functions. However, acquiring an accurate global view of sirtuins in epigenetics will demand that the degree of interplay and redundancy among and between the family members be clearly established. Sirtuins have common targets, which suggest that they cooperate or complement each other according to different stimuli.
Selkeä esimerkki sirtuiinien toisiaan täydentävästä aktiivisuudesta on SIRT1 ja SIRT6 sirtuiinien keskinäinen antagonismi, joka niillä on transkriptiotekijän NF-kB suhteen. Tämä on taas kriittinen säätelytekijä tiettyjen ikääntymiseen, proliferaatioon ja tulehduksiin osallistuvien geenien ilmentymisessä. SIRT6 säätelee NF-kB tietä ja vähentää NF-kB:stä riippuvaa apoptoosia ja ikääntymistä ja täten osoitaa anti-inflammatorisuutta. Jotkut tiedot päinvastoin viittaavat siihen, että estämällä NF-kB:tä SIRT1 vahventaa apoptoosia vasteena TNF alfalle.
A clear example of complementary sirtuin activity is the antagonistic effect that SIRT1 and SIRT6 seem to play on the transcription factor NF‐κB, a critical regulation factor for expression of certain genes involved in aging, proliferation and inflammation. SIRT6 regulates the NF‐κB pathway and decreases NF‐κB‐dependent apoptosis and senescence, thereby playing an anti‐inflammatory role 220. Contrariwise, some data suggest that, by inhibiting NF‐κB, SIRT1 augments apoptosis in response to tumor necrosis factor α (221).
Toinen kiinnostava esimerkki on SIRT1- ja SIRT7- sirtuiinien tekemä polymeraasi I:n säätely. Vasteena eri tyyppisille stresseille säätyy rRNA:n , ribosomaalisen RNA:n transkriptio. Täten SIRT1 ja SIRT7 saattaisivat säädellä polymeraasi I:n transkriptiota erilaisissa stressiolosuhteissa. Mielenkiintoinen seikka on, että SIRT1 vaimentaa polymeraasi I:n deasetyloimalla sen perus- komponettia TAF1, kun taas SIRT7 on osana polymeraasi I:n transkriptionaalisess a koneistossa ja lisää se transkriptioaktiivisuutta vaikuttaen antagonistisesti SIRT1 osuuteen.
• Another interesting example, which we previously mentioned, is the regulation of Pol I by SIRT1 and SIRT7. Transcription of rRNA is regulated in response to different types of stress. Hence, SIRT1 and SIRT7 might regulate Pol I transcription in response to different conditions. Interestingly, nucleolar SIRT1 represses Pol I by deacetylating its basal component TAFI68 61, whereas SIRT7 is part of the Pol I transcriptional machinery and enhances its transcriptional activity, performing an antagonistic role to that of SIRT1 (196).
Mahdollisesti on sirtuiineissa ainakin jonkinlaista keskinäistä funktionaalista toisensakattavuutti ottaen huomioon, että sirtuiinipoistogeeniset (k.o.) ilmentävät vähemmän aggressiivista fenotyyppiä, mitä olisi odottavissa. Esim eräässä tutkimuksessa SIRT1 ja SIRT7-poistogeeniset hiiret osoittivat 50%.n elinkykyisyyttä ja SIRT6 poistogeeniset pysyivät elossa muutaman viikon syntymän jälkeen. SIRT2 ja SIRT6-poistogeeniset näyttivät kärsivän massiivista genomin epävakautta, vaikka SIRT3, SIRT4- ja SIRT7-poistogeeniset osoittautuivat altiimmiksi tumorigeneesille ja kestivät heikommin stressiä.Siitä huolimatta tarvitaan lisätutkimuksia sirtuiinien yhteistoiminnan ja toisiaan täydentävän aktiivisuuden selvittämiseksi, jotta selkenisi jokaisen sirtuiinin osuus genomiseen vakauteen.
• Defining the functional relationships among and between sirtuins remains a critical research objective, as reflected by the aforementioned findings and others. There is probably some functional redundancy among sirtuins, given that sirtuin KO mice exhibit a less aggressive phenotype than one might expect 222. For instance, in one study, SIRT1 KO and SIRT7 KO mice exhibited 50% viability and SIRT6 KO mice survived up to a few weeks after birth. Furthermore, although all of the mice presented metabolic defects, only the SIRT1 KO, SIRT2 KO and SIRT6 KO mice seemed to suffer from massive genome instability, although the SIRT3 KO, SIRT4 KO and SIRT7 KO mice did show some predisposition to tumorigenesis and were less resistant to stress. Regardless, further investigation will be needed to elucidate the cooperative and complementary activities of sirtuins in order to clarify the contribution of each sirtuin to genome stability.
• Acknowledgements We wish to apologize to those colleagues whose work we could not cite in this review due to space limitations. We thank members of the Vaquero group for fruitful discussions. The Vaquero laboratory is funded by the Spanish Ministry of Economy and Competitiveness (formerly MICINN; grant SAF2011‐25860), Marató de TV3 (M12‐CANCER) and the Generalitat de Catalunya. Author contributions LB wrote most of the manuscript. AV wrote part of the manuscript and supervised the whole text.
lisälähteitä: Sirtuiini1 täydentää DNA.n korjaantumista telomeerien ollessa lyhyet. Sirtuiinien merkitys genomin stabiliteetille ja DNA.n integriteetille. http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007356 http://jcb.rupress.org/content/jcb/191/7/1299.full.pdf https://www.ncbi.nlm.nih.gov/pubmed/24014413
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