Involvement of ATM in homologous recombination after end resection and RAD51 nucleofilament formation.
Involvement of ATM in homologous recombination after end resection and RAD51 nucleofilament formation.
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DOI：
10.1093/nar/gkv160
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发表时间：
2015-03-31
影响因子：
14.9
通讯作者：
Mansour WY
中科院分区：
文献类型：
--
作者：
Bakr A;Oing C;Köcher S;Borgmann K;Dornreiter I;Petersen C;Dikomey E;Mansour WY
共济失调毛细血管扩张突变（ATM）是启动同源重组（HR）双链断裂（DSB）修复所必需的。ATM通过刺激CtIP和MRE11的溶核活性，产生3 ' -ssDNA悬垂，进而加载RPA，形成RAD51核丝，从而触发DSB末端切除。在这里，我们首次表明，在RAD51核丝形成后，在HR的后期步骤中也需要ATM。在完成末端切除后，抑制ATM不影响RAD51核丝的形成，但导致HR缺乏，证据如下：(i) S和G2细胞中残余RAD51/γH2AX灶的数量增加，（ii） HR修复底物（pGC）检测到HR效率降低，（iii） SCE率降低，（iv） PARP抑制细胞的放射增敏。研究发现，在异染色质相关的DSB修复中，这种新描述的ATM的作用是不可缺少的，因为当ATM在末端切除后被抑制时，kap1缺失并没有减轻hr缺陷。此外，我们证明ATR可以部分补偿ATM抑制后早期HR步骤的不足，而不是后期HR步骤的不足。综上所述，我们在这里首次描述了ATM不仅需要用于启动，还需要用于完成HR。
Ataxia-telangiectasia mutated (ATM) is needed for the initiation of the double-strand break (DSB) repair by homologous recombination (HR). ATM triggers DSB end resection by stimulating the nucleolytic activity of CtIP and MRE11 to generate 3′-ssDNA overhangs, followed by RPA loading and RAD51 nucleofilament formation. Here we show for the first time that ATM is also needed for later steps in HR after RAD51 nucleofilament formation. Inhibition of ATM after completion of end resection did not affect RAD51 nucleofilament formation, but resulted in HR deficiency as evidenced by (i) an increase in the number of residual RAD51/γH2AX foci in both S and G2 cells, (ii) the decrease in HR efficiency as detected by HR repair substrate (pGC), (iii) a reduced SCE rate and (iv) the radiosensitization of cells by PARP inhibition. This newly described role for ATM was found to be dispensable in heterochromatin-associated DSB repair, as KAP1-depletion did not alleviate the HR-deficiency when ATM was inhibited after end resection. Moreover, we demonstrated that ATR can partly compensate for the deficiency in early, but not in later, steps of HR upon ATM inhibition. Taken together, we describe here for the first time that ATM is needed not only for the initiation but also for the completion of HR.
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影响因子：
4.8
作者：
Mazin, AV;Alexeev, AA;Kowalczykowski, SC
通讯作者：
Kowalczykowski, SC
影响因子：
16
作者：
Peterson SE;Li Y;Wu-Baer F;Chait BT;Baer R;Yan H;Gottesman ME;Gautier J
通讯作者：
Gautier J
影响因子：
5.7
作者：
Mansour, Wael Y.;Bogdanova, Natalia V.;Dahm-Daphi, Jochen
通讯作者：
Dahm-Daphi, Jochen
人CTIP介导DNA终端切除和双链断裂修复的细胞周期控制。
DOI：
10.1074/jbc.m808906200
发表时间：
2009-04-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Huertas P;Jackson SP
通讯作者：
Jackson SP
影响因子：
4.5
作者：
Geuting V;Reul C;Löbrich M
通讯作者：
Löbrich M