Artemis links ATM to double strand break rejoining

被引:76
作者
Jeggo, PA
Löbrich, M
机构
[1] Univ Saarland, D-66421 Homburg, Germany
[2] Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England
基金
英国医学研究理事会;
关键词
radiosensitivity; DNA double strand break repair; non-homologous end-joining; ATM signal transduction pathway; DNA end processing;
D O I
10.4161/cc.4.3.1527
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Ataxia telangiectasia mutated protein (ATM) is a damage response kinase that initiates a signal transduction response to the presence of DNA double strand breaks (DSBs) regulating cell cycle checkpoint arrest and apoptosis. Indirect evidence has argued that A-T cells also harbour a repair defect since unrepaired DSBs can be observed in non-replicating A-T cells after ionising radiation (IR). The basis underlying such a repair defect has remained unexplained, however. Artemis, a nuclease, whose activity is modified by phosphorylation in vitro, was recently identified as a novel ATM substrate. Artemis and ATM function in a common pathway required for the processing of a subset of double stranded DNA ends induced by IR prior to rejoining by non-homologous end-joining (NHEJ). This subset of DSBs are those normally rejoined with slow kinetics. Additional components of the ATM signal transduction pathway, Nbs1, Mre11, H2AX and 53BP1, are also required for this component of DSB repair. This process substantially contributes to survival post irradiation. Our findings add a new dimension to the ATM signal transduction response demonstrating ATM-dependent regulation of an end-processing mechanism that functions during the cell cycle delay effected by ATM.
引用
收藏
页码:359 / 362
页数:4
相关论文
共 24 条
[1]   Ataxia-telangiectasia, an evolving phenotype [J].
Chun, HH ;
Gatti, RA .
DNA REPAIR, 2004, 3 (8-9) :1187-1196
[2]   THE REPAIR OF POTENTIALLY LETHAL DAMAGE IN X-IRRADIATED CULTURES OF NORMAL AND ATAXIA TELANGIECTASIA HUMAN-FIBROBLASTS [J].
COX, R ;
MASSON, WK ;
WEICHSELBAUM, RR ;
NOVE, J ;
LITTLE, JB .
INTERNATIONAL JOURNAL OF RADIATION BIOLOGY, 1981, 39 (04) :357-365
[3]  
Foray N, 1997, INT J RADIAT BIOL, V72, P271, DOI 10.1080/095530097143266
[4]  
HSIEH CL, 1993, J BIOL CHEM, V268, P20105
[5]  
Jeggo PA, 2004, MOL B INT U, P146
[6]   Splitting the ATM: distinct repair and checkpoint defects in ataxia-telangiectasia [J].
Jeggo, PA ;
Carr, AM ;
Lehmann, AR .
TRENDS IN GENETICS, 1998, 14 (08) :312-316
[7]   A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity [J].
Kühne, M ;
Riballo, E ;
Rief, N ;
Rothkamm, K ;
Jeggo, PA ;
Löbrich, M .
CANCER RESEARCH, 2004, 64 (02) :500-508
[8]   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
[9]   The mechanism of vertebrate nonhomologous DNA end joining and its role in V(D)J recombination [J].
Lieber, MR ;
Ma, YM ;
Pannicke, U ;
Schwarz, K .
DNA REPAIR, 2004, 3 (8-9) :817-826
[10]   Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination [J].
Ma, YM ;
Pannicke, U ;
Schwarz, K ;
Lieber, MR .
CELL, 2002, 108 (06) :781-794