title: 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 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.
authors.affiliation: 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.
authors.forename: Luisa
authors.initials: L
authors.lastname: Tasselli
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Xi
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ruth I
authors.initials: RI
authors.lastname: Tennen
authors.affiliation: 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.
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Odrowaz
authors.affiliation: 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.
authors.forename: Federica
authors.initials: F
authors.lastname: Simeoni
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Wei
authors.identifier: 0000-0001-9931-5990
authors.initials: W
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Katrin F
authors.initials: KF
authors.lastname: Chua
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002843:Chromatin / Q000378:metabolism*; D015870:Gene Expression; D020868:Gene Silencing; D057809:HEK293 Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008938:Mitosis; D011499:Protein Processing, Post-Translational; D037761:Sirtuins / Q000737:chemistry / Q000502:physiology*
chemical_list: D002843:Chromatin; D006657:Histones; C516592:SIRT6 protein, human; D037761:Sirtuins