CUP Links DNA Double-Strand Break Sensing to Resection

被引：187

作者：

You, Zhongsheng ^{[1
,2
]}

Shi, Linda Z. ^{[4
]}

Zhu, Quan ^{[3
]}

Wu, Peng ^{[1
]}

Zhang, You-Wei ^{[2
]}

Basilio, Andrew ^{[4
]}

Tonnu, Nina ^{[3
]}

Verma, Inder M. ^{[3
]}

Berns, Michael W. ^{[4
,5
,6
]}

Hunter, Tony ^{[2
]}

机构：

[1] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA

[2] Salk Inst Biol Studies, Mol & Cell Biol Lab, La Jolla, CA 92037 USA

[3] Salk Inst Biol Studies, Genet Lab, La Jolla, CA 92037 USA

[4] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA

[5] Univ Calif Irvine, Beckman Laser Inst, Irvine, CA 92715 USA

[6] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92715 USA

来源：

MOLECULAR CELL | 2009年 / 36卷 / 06期

关键词：

HUMAN CTIP; CHECKPOINT CONTROL; DAMAGE RESPONSE; REQUIRES ATM; ACTIVATION; PROTEIN; BINDING; RECRUITMENT; REPAIR; BRCA1;

D O I：

10.1016/j.molcel.2009.12.002

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：

In response to DNA double-strand breaks (DSBs), cells sense the DNA lesions and then activate the protein kinase ATM. Subsequent DSB resection produces RPA-coated ssDNA that is essential for activation of the DNA damage checkpoint and DNA repair by homologous recombination (HR). However, the biochemical mechanism underlying the transition from DSB sensing to resection remains unclear. Using Xenopus egg extracts and human cells, we show that the tumor suppressor protein CtIP plays a critical role in this transition. We find that CtIP translocates to DSBs, a process dependent on the DSB sensor complex Mre11-Rad50-NBS1, the kinase activity of ATM, and a direct DNA-binding motif in CtIP, and then promotes DSB resection. Thus, CtIP facilitates the transition from DSB sensing to processing: it does so by binding to the DNA at DSBs after DSB sensing and ATM activation and then promoting DNA resection, leading to checkpoint activation and HR.

引用

页码：954 / 969

页数：16

共 45 条

[11] Dimerization of CtIP, a BRCA1- and CtBP-interacting protein, is mediated by an N-terminal coiled-coil motif [J].

Dubin, MJ ;

Stokes, PH ;

Sum, EYM ;

Williams, RS ;

Valova, VA ;

Robinson, PJ ;

Lindeman, GJ ;

Glover, JNM ;

Visvader, JE ;

Matthews, JM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (26) :26932-26938

[12] Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage [J].

Falck, J ;

Coates, J ;

Jackson, SP .

NATURE, 2005, 434 (7033) :605-611

[13] Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes [J].

Greenberg, RA ;

Sobhian, B ;

Pathania, S ;

Cantor, SB ;

Nakatani, Y ;

Livingston, DM .

GENES & DEVELOPMENT, 2006, 20 (01) :34-46

[14] Expression of PCNA-binding domain of CtIP, a motif required for CtIP localization at DNA replication foci, causes DNA damage and activation of DNA damage checkpoint [J].

Gu, Bingnan ;

Chen, Phang-Lang .

CELL CYCLE, 2009, 8 (09) :1409-1420

[15] The DNA damage response: Ten years after [J].

Harper, J. Wade ;

Elledge, Stephen J. .

MOLECULAR CELL, 2007, 28 (05) :739-745

[16] Human CtIP Mediates Cell Cycle Control of DNA End Resection and Double Strand Break Repair [J].

Huertas, Pablo ;

Jackson, Stephen P. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (14) :9558-9565

[17] ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks [J].

Jazayeri, A ;

Falck, J ;

Lukas, C ;

Bartek, J ;

Smith, GCM ;

Lukas, J ;

Jackson, SP .

NATURE CELL BIOLOGY, 2006, 8 (01) :37-U13

[18] Cell-cycle checkpoints and cancer [J].

Kastan, MB ;

Bartek, J .

NATURE, 2004, 432 (7015) :316-323

[19] DNA damage-induced activation of ATM and ATM-dependent signaling pathways [J].

Kurz, EU ;

Lees-Miller, SP .

DNA REPAIR, 2004, 3 (8-9) :889-900

[20] Activation and regulation of ATM kinase activity in response to DNA double-strand breaks [J].

Lee, J-H ;

Paull, T. T. .

ONCOGENE, 2007, 26 (56) :7741-7748

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