https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.13053
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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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.
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