ATM-dependent phosphorylation of ATF2 is required for the DNA damage response

被引:136
作者
Bhoumik, A
Takahashi, S
Breitweiser, W
Shiloh, Y
Jones, N
Ronai, Z [1 ]
机构
[1] Burnham Inst, Signal Transduct Program, La Jolla, CA 92037 USA
[2] Paterson Inst Canc Res, Cell Regulat Lab, Manchester M20 4BX, Lancs, England
[3] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel
关键词
D O I
10.1016/j.molcel.2005.04.015
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
Activating transcription factor 2 (ATF2) is regulated by JNK/p38 in response to stress. Here, we demonstrate that the protein kinase ATM phosphorylates ATF2 on serines 490 and 498 following ionizing radiation (IR). Phosphoantibodies to ATF2 49018 reveal dose-and time-dependent phosphorylation of ATF2 by ATM that results in its rapid colocalization with gamma-H2AX and MRN components into IR-Induced foci (IRIF). Inhibition of ATF2 expression decreased recruitment of Mre11 to IRIF, abrogated S phase checkpoint, reduced activation of ATM, Chk1, and Chk2, and impaired radioresistance. ATF2 requires neither JNK/p38 nor its DNA binding domain for recruitment to IRIF and the S phase checkpoint. Our findings identify a role for ATF2 in the DNA damage response that is uncoupled from its transcriptional activity.
引用
收藏
页码:577 / 587
页数:11
相关论文
共 43 条
[1]   DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation [J].
Bakkenist, CJ ;
Kastan, MB .
NATURE, 2003, 421 (6922) :499-506
[2]   Enhanced phosphorylation of p53 by ATN in response to DNA damage [J].
Banin, S ;
Moyal, L ;
Shieh, SY ;
Taya, Y ;
Anderson, CW ;
Chessa, L ;
Smorodinsky, NI ;
Prives, C ;
Reiss, Y ;
Shiloh, Y ;
Ziv, Y .
SCIENCE, 1998, 281 (5383) :1674-1677
[3]   Identification of the cyclin D1 gene as a target of activating transcription factor 2 in chondrocytes [J].
Beier, F ;
Lee, RJ ;
Taylor, AC ;
Pestell, RG ;
LuValle, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (04) :1433-1438
[4]   An ATF2-derived peptide sensitizes melanomas to apoptosis and inhibits their growth and metastasis [J].
Bhoumik, A ;
Huang, TG ;
Ivanov, V ;
Gangi, L ;
Qiao, RF ;
Woo, SLC ;
Chen, SH ;
Ronai, Z .
JOURNAL OF CLINICAL INVESTIGATION, 2002, 110 (05) :643-650
[5]   Stable suppression of tumorigenicity by virus-mediated RNA interference [J].
Brummelkamp, TR ;
Bernards, R ;
Agami, R .
CANCER CELL, 2002, 2 (03) :243-247
[6]   The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: Linkage of double-strand break repair to the cellular DNA damage response [J].
Carney, JP ;
Maser, RS ;
Olivares, H ;
Davis, EM ;
Le Beau, M ;
Yates, JR ;
Hays, L ;
Morgan, WF ;
Petrini, JHJ .
CELL, 1998, 93 (03) :477-486
[7]   The Mre11 complex is required for ATM activation and the G2/M checkpoint [J].
Carson, CT ;
Schwartz, RA ;
Stracker, TH ;
Lilley, CE ;
Lee, DV ;
Weitzman, MD .
EMBO JOURNAL, 2003, 22 (24) :6610-6620
[8]  
CHEN MH, 1996, HELICOBACTER, V1, P271
[9]   TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage [J].
Cho, SG ;
Bhoumik, A ;
Broday, L ;
Ivanov, V ;
Rosenstein, B ;
Ronai, Z .
MOLECULAR AND CELLULAR BIOLOGY, 2001, 21 (24) :8398-8413
[10]   Requirement of ATM-dependent phosphorylation of BRCA1 in the DNA damage response to double-strand breaks [J].
Cortez, D ;
Wang, Y ;
Qin, J ;
Elledge, SJ .
SCIENCE, 1999, 286 (5442) :1162-1166