SIRT6 Stabilizes DNA-dependent Protein Kinase at Chromatin for DNA Double-strand Break Repair

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2010 Feb 17

PMID 20157594

Citations 166

Authors

Ronald A McCord

Eriko Michishita

Tao Hong

Elisabeth Berber

Lisa D Boxer

Rika Kusumoto

Shenheng Guan

Xiaobing Shi

Or Gozani

Alma L Burlingame

Vilhelm A Bohr

Katrin F Chua

Affiliations

Soon will be listed here.

Abstract

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.

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