The ATM Substrate KAP1 Controls DNA Repair in Heterochromatin: Regulation by HP1 Proteins and Serine 473/824 Phosphorylation

被引：101

作者：

White, David ^{[1
]}

Rafalska-Metcalf, Ilona U. ^{[1
]}

Ivanov, Alexey V. ^{[2
,3
]}

Corsinotti, Andrea ^{[4
]}

Peng, Hongzhuang ^{[1
]}

Lee, Sheng-Chung ^{[5
]}

Trono, Didier ^{[4
]}

Janicki, Susan M. ^{[1
]}

Rauscher, Frank J., III ^{[1
]}

机构：

[1] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

[2] W Virginia Univ, Dept Biochem, Morgantown, WV 26506 USA

[3] W Virginia Univ, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA

[4] Ecole Polytech Fed Lausanne, Frontiers In Genet Natl Ctr Competence Res, CH-1015 Lausanne, Switzerland

[5] Natl Taiwan Univ, Coll Med, Inst Mol Med, Taipei 10764, Taiwan

来源：

MOLECULAR CANCER RESEARCH | 2012年 / 10卷 / 03期

基金：

瑞士国家科学基金会; 欧洲研究理事会;

关键词：

DOUBLE-STRAND BREAKS; ZINC FINGER PROTEINS; HISTONE H2AX; CELL-CYCLE; COREPRESSOR; CHROMATIN; DAMAGE; ASSOCIATION; COLOCALIZES; RECOGNITION;

D O I：

10.1158/1541-7786.MCR-11-0134

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The repair of DNA damage in highly compact, transcriptionally silent heterochromatin requires that repair and chromatin packaging machineries be tightly coupled and regulated. KAP1 is a heterochromatin protein and corepressor that binds to HP1 during gene silencing but is also robustly phosphorylated by Ataxia telangiectasia mutated (ATM) at serine 824 in response to DNA damage. The interplay between HP1-KAP1 binding/ATM phosphorylation during DNA repair is not known. We show that HP1 alpha and unmodified KAP1 are enriched in endogenous heterochromatic loci and at a silent transgene prior to damage. Following damage, gamma H2AX and pKAP1-s824 rapidly increase and persist at these loci. Cells that lackHP1 fail to form discreet pKAP1-s824 foci after damage but levels are higher and more persistent. KAP1 is phosphorylated at serine 473 in response to DNA damage and its levels are also modulated by HP1. Unlike pKAP1-s824, pKAP1-s473 does not accumulate at damage foci but is diffusely localized in the nucleus. While HP1 association tempers KAP1 phosphorylation, this interaction also slows the resolution of gamma H2AX foci. Thus, HP1-dependent regulation of KAP1 influences DNA repair in heterochromatin. Mol Cancer Res; 10(3); 401-14. (C)2011 AACR.

引用

页码：401 / 414

页数：14

共 37 条

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