TY - JOUR
T1 - SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence
AU - Tasselli, Luisa
AU - Xi, Yuanxin
AU - Zheng, Wei
AU - Tennen, Ruth I.
AU - Odrowaz, Zaneta
AU - Simeoni, Federica
AU - Li, Wei
AU - Chua, Katrin F.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84962094354&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84962094354&partnerID=8YFLogxK
U2 - 10.1038/nsmb.3202
DO - 10.1038/nsmb.3202
M3 - Article
C2 - 27043296
AN - SCOPUS:84962094354
SN - 1545-9993
VL - 23
SP - 434
EP - 440
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 5
ER -