https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.13053
Sirtuin-dependent epigenetic regulation in the maintenance of genome integrity
First published: 15 September 2014
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.
ERITYISETI SIRT2:
SIRT2
Vaikka SIRT2 on pääasiassa lokalisoitunut sytoplasmaan, se pystyy
deasetyloimaan H4K16Ac ja vähemmässä määrin myös H3K9Ac.
RNA-interferenssitutkimuksin on osoitettu, että SIRT2:n kato korreloi
korkeisiin H4K16Ac:n pitoisuuksiin, mikä on analogista SIRT1:n kadon
kanssa.
Tämä SIRT2-aktiivisuus on evoluution aikana konservoitunut ja viittaa
siihen , että myös hiivan SIRT2 ortologi Hst2p olisi myös spesifinen
H4K16Ac:lle. Mutta H4K16Ac deasetylaatio SIRT2:n avulla ei kuitenkaan
johda heterokromatiinin muodostukseen, vaan sen sijaan hyvin tärkeään
tehtävään solusyklin kontrolloimisessa. ( Tämä on osoitettu hiiren
alkion fibroblasteilla verrattaessa Sirt2-/- ja Sirt1-/- fibroblasteja
mitoosissa: mitoottinen Sirt2-/- osoitti H4K16Ac hypoasetylaatiota,
mutta tätä ei ilmentynyt Sirt1-/- fibroblasteissa).
Mielenkiintoinen huomio oli, että H4K16Ac säätyy tiukasti solusyklin
aikana. Sen huippupitoisuus on S-faasin aikana ja sen pitoisuus laskee
hyvin vahvasti G2/M siirtymässä. SIRT2 esiintyy sytoplasmassa koko
solusyklin aikana muulloin paitsi G2/M transitiossa, jolloin se
sukkuloituu tuman puolelle deasetyloimaan kaiken H4K16Ac:n ennen
mitoosiin (M) siirtymistä. .
• Despite being localized chiefly in
the cytoplasm, SIRT2 specifically deacetylates H4K16Ac and, to a much
lesser extent, H3K9Ac. RNAi experiments show that loss of SIRT2
correlates to high levels of H4K16Ac, analogously to loss of SIRT1 (21).
This activity has been conserved over evolution, as indicated by the
fact that the SIRT2 yeast ortholog Hst2p is also highly specific for
H4K16Ac. Unlike SIRT1, deacetylation of H4K16Ac by SIRT2 is not related
to heterochromatin formation but instead has a very important role in cell cycle control, as
evidenced by the fact that Sirt2−/− mouse embryonic fibroblasts (MEFs)
exhibit H4K16Ac hypoacetylation during mitosis, whereas Sirt1−/− MEFs do
not 21. Interestingly, H4K16Ac is tightly regulated during the cell
cycle: its levels peak during S phase and drop dramatically in the G2/M
transition. SIRT2 is present in the cytoplasm throughout the cell cycle
except during the G2/M transition, when it is shuttled to the nucleus
where it deacetylates H4K16Ac globally before entering mitosis (21, 29,
79
•
Alunperin tulkittiin tämä globaali deasetylaatio mitoosiin siirtymisen
edellytykseksi ottaen huomioon tämän histonitunnuksen relevanssi
kromatiinin tiivistymisen estämisessä. Kuitenkin jatkotutkimukset
osoittivat, että SIRT2:lla tapahtuva H4K16Ac:n deasetylaatio on
varsinaisesti ylin säätö H4K20me1-kertymälle, monometyloidun histonin
kertymän mahdollisuudelle..
Itseasiassa sitten ehdotettiin useita vuosia H4K16Ac -ja H4K20me1-
merkkautuneitten histoneitten antagonismia, vastavaikutteisuutta. Tätä
perusteltiin siten, että H4K16Ac omaa monometyloidun H4K20me1
metyylitransferaasin (HMT, PR-SET) aktiivisuuden estävää
ominaisuutta. Kuitenkin tällainen oletettu antagonismi osoittautui
ilmenevän vain G2/M:ssä ja taas muissa yhteyksissä H4K16Ac ja
H4K20me1 näyttivät sijoittautuneen yhdessä samaan kohtaan .
Siitä huolimatta tämän (G2/M vaiheen) antagonismin merkitsevyys piilee
siinä relevantissa roolissa, mikä H4K20-mono-, di- tai trimetylaatiolla
on solusyklin kontrolliin, kehitykseen, kromosomin tiivistymiseen,
DNA:n korjaussignalointiin ja genomin stabiliteet tiin. •
This global deacetylation of H4K16Ac was originally interpreted as a
prerequisite for mitotic entry, given the relevance of this mark in the
inhibition of chromatin compaction. However, subsequent studies showed
that deacetylation of H4K16Ac by SIRT2 during G2/M is actually paramount
for regulating deposition of H4K20me1 31. In fact, an antagonism
between H4K16Ac and H4K20me1 was proposed several years ago 32, based on
the inhibitory effect that H4K16Ac has on the methyltransferase
activity of the H4K20me1 HMT, PR‐SET7 (31, 32). However, this antagonism
seems to occur only in G2/M; in other contexts, H4K16Ac and H4K20me1
have been shown to localize together 78. Nonetheless, the significance
of this antagonism lies in the relevant role of H4K20 mono‐, di‐ or
tri‐methylation in the control of cell cycle progression, development,
chromosome compaction, DNA repair signaling and genome stability (7
9-83).
H4K20me1 , lysiiniinsä 20 monometyloitunut H4.
H4K20me1 on esimerkiksi essentielli kromatiinin tiivistymisessä
mitoosin aikana ja solusyklin progredioitumisen aikana.
SIRT2 varsinaisesti säätelee H4K20me1- PR-SET7
histonimetyylitransferaasin aktiivisuutta eikä ainoastaan
deasetyloimalla histonia H4K16Ac, vaan myös suoraan moduloimalla
entsyymin PR SET7 aktiivisuutta ja dynamiikkaa. Saatujen tietojen
mukaan tämä säätely on suoraan vaikuttamassa G2/M-tarkistuskohdan
kontrollia.
G2/M:n aikaisessa stressissä SIRT2 sitoutuu vahvasti (histonia
metyloivaan) PR-SET/7-entsyymiin , mikä johtaa lisääntyneeseen
H4K20me1:n määrään, ja tämä taas korreloi solusyklin
blokeerautumiseen G2/M kohdassa stressin aikana.
Lisäksi SIRT2 on hyvin tärkeä solusyklille ja nämä vaikutukset ulottuvat
yli G2/M -transitiovaiheessa tapahtuvan H4K16- ja H4K20- histonien
säätelyn.
SIRT2 säätelee muita proteiineja myös muissa solusyklifaaseissa.
• For instance, H4K20me1 is essential for
chromatin condensation during mitosis and cell cycle progression. As we
discuss later, SIRT2 actually regulates the H4K20me1 activity of
PR‐SET7, not only by deacetylating H4K16Ac but also by directly
modulating the activity and dynamics of PR‐SET7. Data show that this
regulation is directly involved in G2/M checkpoint control. Under stress
during G2/M, SIRT2 binds strongly to PR‐SET7, leading to an increase in
H4K20me1, which correlates to blocking of the cell cycle at G2/M 31.
Moreover, SIRT2 is very important in the cell cycle and extends beyond
regulation of H4K16 and H4K20 in G2/M: it also helps regulate important
proteins in other phases (77), (84-86).
....
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.
Lisäys: Genecards_** PR-SET7 https://www.genecards.org/cgi-bin/carddisp.pl?gene=KMT5A&keywords=PR-SET7
- GeneCards Symbol:
KMT5A
2
-
Lysine Methyltransferase 5A
2
3
5
-
PR-Set7
2
3
4
5
-
SET07
2
3
4
5
-
SET8
2
3
4
5
-
SETD8
3
4
5
-
SET Domain Containing (Lysine Methyltransferase) 8
2
3
-
Lysine (K)-Specific Methyltransferase 5A
2
3
-
Histone-Lysine N-Methyltransferase KMT5A
3
4
-
PR/SET Domain-Containing Protein 07
3
4
-
N-Lysine Methyltransferase KMT5A
3
4
-
SET Domain-Containing Protein 8
3
4
-
Lysine N-Methyltransferase 5A
3
4
Post-translational modifications for KMT5A Gene
-
Acetylated at Lys-162; does not affect methyltransferase activity.
Deacetylated at Lys-162 possibly by SIRT2; does not change methyltransferase activity.
(
Q9NQR1-KMT5A_HUMAN )
-
Ubiquitinated and degraded by the DCX(DTL) complex.
(
Q9NQR1-KMT5A_HUMAN )
-
Ubiquitination at Lys236 and Lys275
(
NX_Q9NQR1 [NX_Q9NQR1-1]
)
-
Modification sites at PhosphoSitePlus
(
Q9NQR1 )
-
Glycosylation from GlyGen (Q9NQR1) 1 site, 1 O-linked glycan (1 site)
Protein-lysine N-methyltransferase that monomethylates both histones and non-histone proteins (PubMed:12086618,
Specifically monomethylates 'Lys-20' of histone H4 (H4K20me1) (PubMed:12086618, 12121615,
H4K20me1 is enriched during mitosis and represents a specific tag for epigenetic transcriptional repression (PubMed:12086618,
Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes (PubMed:12086618
Required
for cell proliferation, probably by contributing to the maintenance of
proper higher-order structure of DNA during mitosis (PubMed:12086618,
Involved in chromosome condensation and proper cytokinesis (PubMed:12086618, 12121615,
Nucleosomes are preferred as substrate compared to free histones (PubMed:12086618, 12121615,
Mediates monomethylation of p53/TP53 at 'Lys-382', leading to repress p53/TP53-target genes (PubMed:17707234).
Plays a negative role in TGF-beta response regulation and a positive role in
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