Kruppel-associated Box (KRAB)-associated Co-repressor (KAP-1) Ser-473 Phosphorylation Regulates Heterochromatin Protein 1β (HP1-β) Mobilization and DNA Repair in Heterochromatin

被引:43
作者
Bolderson, Emma [1 ,5 ]
Savage, Kienan I. [1 ,2 ]
Mahen, Robert [3 ]
Pisupati, Venkat [3 ]
Graham, Mark E. [4 ]
Richard, Derek J. [5 ]
Robinson, Phillip J. [4 ]
Venkitaraman, Ashok R. [3 ]
Khanna, Kum Kum [1 ]
机构
[1] Queensland Inst Med Res, Signal Transduct Lab, Brisbane, Qld 4029, Australia
[2] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT9 7BL, Antrim, North Ireland
[3] Hutchison MRC Res Ctr, Med Res Council MRC Canc Cell Unit, Cambridge CB2 OXZ, England
[4] Univ Sydney, Cell Signalling Unit, Childrens Med Res Inst, Westmead, NSW 2145, Australia
[5] Queensland Univ Technol, Fac Hlth, Brisbane, Qld 4059, Australia
基金
英国医学研究理事会; 澳大利亚研究理事会;
关键词
DOUBLE-STRAND BREAKS; HOMOLOGOUS RECOMBINATION REPAIR; IN-VIVO; DAMAGE RESPONSE; HP1; PROTEINS; DYNAMIN-I; BINDING; COREPRESSOR; DOMAIN; ATM;
D O I
10.1074/jbc.M112.368381
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The DNA damage response encompasses a complex series of signaling pathways that function to regulate and facilitate the repair of damaged DNA. Recent studies have shown that the repair of transcriptionally inactive chromatin, named heterochromatin, is dependent upon the phosphorylation of the co-repressor, Kruppel-associated box (KRAB) domain-associated protein (KAP-1), by the ataxia telangiectasia-mutated (ATM) kinase. Co-repressors, such as KAP-1, function to regulate the rigid structure of heterochromatin by recruiting histone-modifying enzymes, such HDAC1/2, SETDB1, and nucleosome-remodeling complexes such as CHD3. Here, we have characterized a phosphorylation site in the HP1-binding domain of KAP-1, Ser-473, which is phosphorylated by the cell cycle checkpoint kinase Chk2. Expression of a nonphosphorylatable S473A mutant conferred cellular sensitivity to DNA-damaging agents and led to defective repair of DNA double-strand breaks in heterochromatin. In addition, cells expressing S473A also displayed defective mobilization of the HP1-beta chromodomain protein. The DNA repair defect observed in cells expressing S473A was alleviated by depletion of HP1-beta, suggesting that phosphorylation of KAP-1 on Ser-473 promotes the mobilization of HP1-beta from heterochromatin and subsequent DNA repair. These results suggest a novel mechanism of KAP-1-mediated chromatin restructuring via Chk2-regulated HP1-beta exchange from heterochromatin, promoting DNA repair.
引用
收藏
页码:28122 / 28131
页数:10
相关论文
共 36 条
  • [21] Heterochromatin protein 1 is recruited to various types of DNA damage
    Luijsterburg, Martijn S.
    Dinant, Christoffel
    Lans, Hannes
    Stap, Jan
    Wiernasz, Elzbieta
    Lagerwerf, Saskia
    Warmerdam, Daniel O.
    Lindh, Michael
    Brink, Maartje C.
    Dobrucki, Jurek W.
    Aten, Jacob A.
    Fousteri, Maria I.
    Jansen, Gert
    Dantuma, Nico P.
    Vermeulen, Wim
    Mullenders, Leon H. F.
    Houtsmuller, Adriaan B.
    Verschure, Pernette J.
    van Driel, Roel
    [J]. JOURNAL OF CELL BIOLOGY, 2009, 185 (04) : 577 - 586
  • [22] Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro
    Matsuoka, S
    Rotman, G
    Ogawa, A
    Shiloh, Y
    Tamai, K
    Elledge, SJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (19) : 10389 - 10394
  • [23] DNA double-strand break repair within heterochromatic regions
    Murray, Johanne M.
    Stiff, Tom
    Jeggo, Penny A.
    [J]. BIOCHEMICAL SOCIETY TRANSACTIONS, 2012, 40 : 173 - 178
  • [24] 53BP1-dependent robust localized KAP-1 phosphorylation is essential for heterochromatic DNA double-strand break repair
    Noon, Angela T.
    Shibata, Atsushi
    Rief, Nicole
    Loebrich, Markus
    Stewart, Grant S.
    Jeggo, Penelope A.
    Goodarzi, Aaron A.
    [J]. NATURE CELL BIOLOGY, 2010, 12 (02) : 177 - U191
  • [25] Determination of substrate motifs for human Chk1 and hCds1/Chk2 by the oriented peptide library approach
    O'Neill, T
    Giarratani, L
    Chen, P
    Iyer, L
    Lee, CH
    Bobiak, M
    Kanai, F
    Zhou, BB
    Chung, JH
    Rathbun, GA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (18) : 16102 - 16115
  • [26] Hetero-oligomerization among the TIF family of RBCC/TRIM domain-containing nuclear cofactors: A potential mechanism for regulating the switch between coactivation and corepression
    Peng, HZ
    Feldman, I
    Rauscher, FJ
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 2002, 320 (03) : 629 - 644
  • [27] Single-stranded DNA-binding protein hSSB1 is critical for genomic stability
    Richard, Derek J.
    Bolderson, Emma
    Cubeddu, Liza
    Wadsworth, Ross I. M.
    Savage, Kienan
    Sharma, Girdhar G.
    Nicolette, Matthew L.
    Tsvetanov, Sergie
    McIlwraith, Michael J.
    Pandita, Raj K.
    Takeda, Shunichi
    Hay, Ronald T.
    Gautier, Jean
    West, Stephen C.
    Paull, Tanya T.
    Pandita, Tej K.
    White, Malcolm F.
    Khanna, Kum Kum
    [J]. NATURE, 2008, 453 (7195) : 677 - U13
  • [28] Ryan RF, 1999, MOL CELL BIOL, V19, P4366
  • [29] The KAP1 corepressor functions to coordinate the assembly of de novo HP1-demarcated microenvironments of heterochromatin required for KRAB zinc finger protein-mediated transcriptional repression
    Sripathy, Smitha P.
    Stevens, Jessica
    Schultz, David C.
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (22) : 8623 - 8638
  • [30] Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells
    Tjeertes, Jorrit V.
    Miller, Kyle M.
    Jackson, Stephen P.
    [J]. EMBO JOURNAL, 2009, 28 (13) : 1878 - 1889