SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence

Abstract

Pericentric heterochromatin silencing at mammalian centromeres is essential for mitotic fidelity and genomic stability. Defective pericentric silencing is observed in senescent cells, aging tissues, and mammalian tumors, but the underlying mechanisms and functional consequences of these defects are unclear. Here, we uncover a pivotal role of the human SIRT6 enzyme in pericentric transcriptional silencing, and show that this function protects against mitotic defects, genomic instability, and cellular senescence. At pericentric heterochromatin, SIRT6 promotes deacetylation of a new substrate, histone H3 lysine K18 (H3K18), and inactivation of SIRT6 in cells leads to H3K18 hyperacetylation and aberrant accumulation of pericentric transcripts. Strikingly, RNAi-depletion of these transcripts rescues the mitotic and senescence phenotypes of SIRT6-deficient cells. Together, our findings reveal a new function for SIRT6 and H3K18Ac regulation at heterochromatin, and demonstrate the pathogenic role of de-regulated pericentric transcription in aging- and cancer- related cellular dysfunction.

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

“…characterized as a highly specific H3 deacetylase that targets Lys-9 (H3K9), Lys-56 (H3K56), and Lys-18 (H3K18) (Fig. 2) (86,121,122,140,171), as confirmed by Wang et al through a novel approach to generate nucleosomes specifically acetylated on a single specific site (191). It has been hypothesized that, under oxidative and nitrosative stress, SIRT6 activity can be regulated via reactive nitrogen species-mediated posttranslational modifications (71).…”

“…Indeed, the SIRT6-dependent heterochromatin packaging of heterochromatin at LINE-1 retroelements suppresses the transposition, a function that can be compromised during aging (181). Furthermore, SIRT6-dependent H3 Lys-18 deacetylation maintains pericentric heterochromatin silencing (171,172). Moreover, accumulation of pathological pericentric transcripts in SIRT6-deficient cells is involved in aging, genomic instability, and cellular senescence (171,172).…”

Sirt7 inhibits Sirt1-mediated activation of Suv39h1

“…In contrast, Sirt7 did not affect expression of satellite repeats despite the fact that Sirt7 is able to specifically deacetylate H3K18 [4,5]. The lack of Sirt7 influence on satellite repeats transcription is puzzling in view of the higher Suv39h1 recruitment to the pericentric heterochromatin demonstrated in our paper and requires further investigation.…”

“…The nuclear sirtuin Sirt6 was recently shown to promote pericentric heterochromatin condensation and silencing of pericentric satellite repeat elements by deacetylation of lysine 18 of H3 (H3K18 [5];). In contrast, Sirt7 did not affect expression of satellite repeats despite the fact that Sirt7 is able to specifically deacetylate H3K18 [4,5].…”

“…Regulation of such different biological functions is mediated by deacetylation of critical cellular targets such as p53, FOXO and other transcription factors and enzymes as well as by the control of chromatin dynamics in response to internal or external stimuli. Sirtuins deacetylate histones H1, H3, H4 at different lysine residues thus contributing to gene silencing and heterochromatin formation [2–5]. Sirtuins also control activation of histone modifiers such as methyltransferases and acetyltransferases, thereby regulating a complex network promoting chromatin compaction [3].…”