SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair.
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.
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ronald A
RA
McCord
Eriko
E
Michishita
Tao
T
Hong
Elisabeth
E
Berber
Lisa D
LD
Boxer
Rika
R
Kusumoto
Shenheng
S
Guan
Xiaobing
X
Shi
Or
O
Gozani
Alma L
AL
Burlingame
Vilhelm A
VA
Bohr
Katrin F
KF
Chua
D000107:Acetylation; D034961:Antigens, Nuclear / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002474:Cell-Free System / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000502:physiology; D004265:DNA Helicases / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D000072200:Ku Autoantigen; D009154:Mutation / Q000502:physiology; D009707:Nucleosomes / Q000378:metabolism; D034622:RNA Interference; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic
D034961:Antigens, Nuclear; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D009707:Nucleosomes; D029701:Saccharomyces cerevisiae Proteins; D051747:DNA-Activated Protein Kinase; D004706:Endodeoxyribonucleases; C064579:I-Ppo endonuclease; C037725:SCEI protein, S cerevisiae; D015252:Deoxyribonucleases, Type II Site-Specific; C516592:SIRT6 protein, human; D037761:Sirtuins; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen