DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities.
DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities.
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DOI：
10.1016/j.molcel.2013.11.003
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发表时间：
2014-01-09
期刊：
影响因子：
16
通讯作者：
Tainer, John A.
中科院分区：
文献类型：
--
作者：
Shibata, Atsushi;Moiani, Davide;Arvai, Andrew S.;Perry, Jefferson;Harding, Shane M.;Genois, Marie-Michelle;Maity, Ranjan;van Rossum-Fikkert, Sari;Kertokalio, Aryandi;Romoli, Filippo;Ismail, Amani;Ismalaj, Ermal;Petricci, Elena;Neale, Matthew J.;Bristow, Robert G.;Masson, Jean-Yves;Wyman, Claire;Jeggo, Penny A.;Tainer, John A.
MRE 11-RAD 50-NBS 1（MRN）复合物中的MRE 11在DNA双链断裂修复（DSBR）、检测和信号传导中起作用;然而，其内切和外切核酸酶活性如何通过非同源末端连接（NHEJ）与同源重组（HR）调节DSB修复仍然是个谜。在这里，我们采用了基于结构的设计与集中的化学库，以发现特定的MRE 11内切或外切核酸酶抑制剂。使用这些抑制剂，我们研究了辐射暴露后G2中产生的DSB的修复途径选择。虽然内切或外切核酸酶抑制损害辐射诱导的RPA染色质结合，表明减少切除，抑制剂令人惊讶地指导不同的修复结果。核酸内切酶抑制促进NHEJ代替HR，而核酸外切酶抑制赋予修复缺陷。总的来说，这些结果描述了核酸酶特异性MRE 11抑制剂，定义了DSB修复中不同的核酸酶作用，并支持MRE 11核酸内切酶启动切除的机制，从而许可HR，然后是MRE 11 exo和EXO 1/BLM双向切除，朝向和远离DNA末端，其提交给HR。
MRE11 within the MRE11-RAD50-NBS1 (MRN) complex acts in DNA double-strand break repair (DSBR), detection and signaling; yet, how its endo- and exonuclease activities regulate DSB repair by non-homologous end-joining (NHEJ) versus homologous recombination (HR) remains enigmatic. Here we employed structure-based design with a focused chemical library to discover specific MRE11 endo- or exonuclease inhibitors. With these inhibitors we examined repair pathway choice at DSBs generated in G2 following radiation exposure. Whilst endo- or exonuclease inhibition impairs radiation-induced RPA chromatin binding, suggesting diminished resection, the inhibitors surprisingly direct different repair outcomes. Endonuclease inhibition promotes NHEJ in lieu of HR, whilst exonuclease inhibition confers a repair defect. Collectively, the results describe nuclease-specific MRE11 inhibitors, define distinct nuclease roles in DSB repair, and support a mechanism whereby MRE11 endonuclease initiates resection, thereby licensing HR followed by MRE11 exo and EXO1/BLM bidirectional resection towards and away from the DNA end, which commits to HR.
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