Tasselli Luisa, Xi Yuanxin, Zheng Wei, Tennen Ruth I, Odrowaz Zaneta, Simeoni Federica, Li Wei, Chua Katrin F
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Geriatric Research, Education, and Clinical Center, Veterans Affairs, Palo Alto Health Care System, Palo Alto, California, USA.
Nat Struct Mol Biol. 2016 May;23(5):434-40. doi: 10.1038/nsmb.3202. Epub 2016 Apr 4.
Pericentric heterochromatin silencing at mammalian centromeres is essential for mitotic fidelity and genomic stability. Defective pericentric silencing has been observed in senescent cells, aging tissues, and mammalian tumors, but the underlying mechanisms and functional consequences of these defects are unclear. Here, we uncover an essential role of the human SIRT6 enzyme in pericentric transcriptional silencing, and we show that this function protects against mitotic defects, genomic instability, and cellular senescence. At pericentric heterochromatin, SIRT6 promotes deacetylation of a new substrate, residue K18 of histone H3 (H3K18), and inactivation of SIRT6 in cells leads to H3K18 hyperacetylation and aberrant accumulation of pericentric transcripts. Strikingly, depletion of these transcripts through RNA interference rescues the mitotic and senescence phenotypes of SIRT6-deficient cells. Together, our findings reveal a new function for SIRT6 and regulation of acetylated H3K18 at heterochromatin, and demonstrate the pathogenic role of deregulated pericentric transcription in aging- and cancer-related cellular dysfunction.
哺乳动物着丝粒处的着丝粒周围异染色质沉默对于有丝分裂保真度和基因组稳定性至关重要。在衰老细胞、衰老组织和哺乳动物肿瘤中已观察到着丝粒周围沉默缺陷，但其潜在机制和这些缺陷的功能后果尚不清楚。在此，我们揭示了人类SIRT6酶在着丝粒周围转录沉默中的重要作用，并表明该功能可防止有丝分裂缺陷、基因组不稳定和细胞衰老。在着丝粒周围异染色质处，SIRT6促进一种新底物——组蛋白H3（H3K18）的K18残基去乙酰化，细胞中SIRT6失活会导致H3K18超乙酰化和着丝粒周围转录本异常积累。引人注目的是，通过RNA干扰去除这些转录本可挽救SIRT6缺陷细胞的有丝分裂和衰老表型。总之，我们的发现揭示了SIRT6的新功能以及异染色质上乙酰化H3K18的调控，并证明了着丝粒周围转录失调在衰老和癌症相关细胞功能障碍中的致病作用。
