Sirt7 stabilizes rDNA heterochromatin through recruitment of DNMT1 and Sirt1

Sirt7 inhibits Sirt1-mediated activation of Suv39h1

“…H3K9me3 levels were clearly increased in Sirt7 knockout MEFs (Figure 2(A)) together with a higher number of HP1 alpha foci (HP1α), a known component of constitutive heterochromatin (Figure 2(B)). Notably, Sirt7 KO cells showed a disrupted nucleolar structure as visualized by staining for the nucleolar marker nucleophosmin (NPM), consistent with previous reports (Figure 2(A) [21];). To investigate whether the higher level of H3K9me3 observed in Sirt7 knockout cells is indeed due to increased activity of Suv39h1, we performed Suv39h1 and Sirt7 knock down experiments and western blot analyzes in U2OS cells.…”

“…In contrast, Sirt7 promotes Sirt1 binding to rDNA together with DNA methyltransferase 1 (DNMT1) for induction of heterochromatin formation [21]. To further elucidate the role of Sirt7 on Sirt1, we wanted to explore whether Sirt7 also controls other Sirt1 effects on heterochromatin.…”

“…In the absence of Sirt7, Sirt1 is constantly deacetylated and causes increased Suv39h1 activity at constitutive pericentric heterochromatin resulting in high levels of H3K9me3 and disturbed heterochromatin structure (4(Bb)). Interestingly, the lack of Sirt7 seems to have different effects on rDNA repeats, which contain facultative heterochromatin [21]. At rDNA repeats the absence of Sirt7 leads to diminished DNMT1 and Sirt1 recruitment causing chromatin relaxation and rDNA instability (Figure 4(Bc), 4(Bd)).…”

“…At rDNA repeats the absence of Sirt7 leads to diminished DNMT1 and Sirt1 recruitment causing chromatin relaxation and rDNA instability (Figure 4(Bc), 4(Bd)). We reason that such differences might be explained by the inability of Sirt1 to get recruited to rDNA repeats in the absence of Sirt7 even when catalytically hyperactive Sirt1 is present (Figure 4(Bc), 4(Bd)) [21]. At present the significance of such opposite regulation of different chromatin regions remains elusive but is obviously biologically important, as illustrated by alterations of both constitutive and facultative nucleolar rDNA heterochromatin in Sirt7 knockout cells.…”

“…The clear increase of constitutive heterochromatin in Sirt7 mutant cells seems to be in contrast to increased relaxation of facultative rDNA heterochromatin, which is also apparent in Sirt7 KO cells. Relaxation of rDNA heterochromatin causes loss of rDNA repeats and might eventually result in genomic instability, a condition promoting cellular aging [21]. Hence, a pivotal role of Sirt7 for controlling genomic stability emerges, although the mechanisms by which this effect is achieved differ between different chromosomal locations.…”