TY - JOUR

T1 - SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair

AU - McCord, Ronald A

AU - Michishita, Eriko

AU - Hong, Tao

AU - Berber, Elisabeth

AU - Boxer, Lisa D

AU - Kusumoto, Rika

AU - Guan, Shenheng

AU - Shi, Xiaobing

AU - Gozani, Or

AU - Burlingame, Alma L

AU - Bohr, Vilhelm A

AU - Chua, Katrin F

PY - 2009/1/1

Y1 - 2009/1/1

N2 - The Sir2 chromatin regulatory factor links maintenance of genomic stability to life span extension in yeast. The mammalian Sir2 family member SIRT6 has been proposed to have analogous functions, because SIRT6-deficiency leads to shortened life span and an aging-like degenerative phenotype in mice, and SIRT6 knockout cells exhibit genomic instability and DNA damage hypersensitivity. However, the molecular mechanisms underlying these defects are not fully understood. Here, we show that SIRT6 forms a macromolecular complex with the DNA double-strand break (DSB) repair factor DNA-PK (DNA-dependent protein kinase) and promotes DNA DSB repair. In response to DSBs, SIRT6 associates dynamically with chromatin and is necessary for an acute decrease in global cellular acetylation levels on histone H3 Lysine 9. Moreover, SIRT6 is required for mobilization of the DNA-PK catalytic subunit (DNA-PKcs) to chromatin in response to DNA damage and stabilizes DNA-PKcs at chromatin adjacent to an induced site-specific DSB. Abrogation of these SIRT6 activities leads to impaired resolution of DSBs. Together, these findings elucidate a mechanism whereby regulation of dynamic interaction of a DNA repair factor with chromatin impacts on the efficiency of repair, and establish a link between chromatin regulation, DNA repair, and a mammalian Sir2 factor.

AB - The Sir2 chromatin regulatory factor links maintenance of genomic stability to life span extension in yeast. The mammalian Sir2 family member SIRT6 has been proposed to have analogous functions, because SIRT6-deficiency leads to shortened life span and an aging-like degenerative phenotype in mice, and SIRT6 knockout cells exhibit genomic instability and DNA damage hypersensitivity. However, the molecular mechanisms underlying these defects are not fully understood. Here, we show that SIRT6 forms a macromolecular complex with the DNA double-strand break (DSB) repair factor DNA-PK (DNA-dependent protein kinase) and promotes DNA DSB repair. In response to DSBs, SIRT6 associates dynamically with chromatin and is necessary for an acute decrease in global cellular acetylation levels on histone H3 Lysine 9. Moreover, SIRT6 is required for mobilization of the DNA-PK catalytic subunit (DNA-PKcs) to chromatin in response to DNA damage and stabilizes DNA-PKcs at chromatin adjacent to an induced site-specific DSB. Abrogation of these SIRT6 activities leads to impaired resolution of DSBs. Together, these findings elucidate a mechanism whereby regulation of dynamic interaction of a DNA repair factor with chromatin impacts on the efficiency of repair, and establish a link between chromatin regulation, DNA repair, and a mammalian Sir2 factor.

KW - Acetylation

KW - Antigens, Nuclear

KW - Cell Nucleus

KW - Cell-Free System

KW - Chromatin

KW - Chromatin Immunoprecipitation

KW - Comet Assay

KW - DNA Breaks, Double-Stranded

KW - DNA Damage

KW - DNA Helicases

KW - DNA Repair

KW - DNA-Activated Protein Kinase

KW - DNA-Binding Proteins

KW - Deoxyribonucleases, Type II Site-Specific

KW - Endodeoxyribonucleases

KW - Hela Cells

KW - Histones

KW - Humans

KW - Immunoprecipitation

KW - Mutation

KW - Nucleosomes

KW - RNA Interference

KW - Saccharomyces cerevisiae Proteins

KW - Sirtuins

KW - Transduction, Genetic

M3 - Journal article

C2 - 20157594

VL - 1

SP - 109

EP - 121

JO - Aging

JF - Aging

SN - 1945-4589

IS - 1

ER -