Sensing and Processing of DNA Interstrand Crosslinks by the Mismatch Repair Pathway.
Sensing and Processing of DNA Interstrand Crosslinks by the Mismatch Repair Pathway.
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DOI：
10.1016/j.celrep.2017.10.032
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发表时间：
2017-10-31
期刊：
影响因子：
8.8
通讯作者：
Gautier J
中科院分区：
文献类型：
--
作者：
Kato N;Kawasoe Y;Williams H;Coates E;Roy U;Shi Y;Beese LS;Schärer OD;Yan H;Gottesman ME;Takahashi TS;Gautier J
在非分裂细胞中修复的DNA链间交联（ICLs）必须独立于复制相关的DNA解绕而被识别。使用爪蟾卵的无细胞提取物，既不支持复制也不支持转录，我们建立了icl被错配修复（MMR）机制识别和处理。我们发现，ICL修复需要MutSα (MSH2-MSH6)和MSH6中的错配识别FXE基序，这强烈表明MutSα作为ICL传感器起作用。MutSα招募MutLα和EXO1到ICL病变，这两种核酸酶的催化活性对ICL修复至关重要。正如对DNA解旋独立识别过程的预期，我们证明了最小扭曲的icl不能被MMR机制识别和修复。这表明ICL结构是DNA复制之外修复效率的关键决定因素。Kato等人发现了一种独立于DNA复制和转录的ICL识别机制。在缺乏这些过程的情况下，ICLs被MMR机制识别和修复。MutSα对ICL识别至关重要，而MutLα和EXO1在ICL修复过程中参与关键的下游溶核步骤。
DNA interstrand crosslinks (ICLs) that are repaired in non-dividing cells must be recognized independently of replication-associated DNA unwinding. Using cell-free extracts from Xenopus eggs that support neither replication nor transcription, we establish that ICLs are recognized and processed by the mismatch repair (MMR) machinery. We find that ICL repair requires MutSα (MSH2–MSH6) and the mismatch recognition FXE motif in MSH6, strongly suggesting that MutSα functions as an ICL sensor. MutSα recruits MutLα and EXO1 to ICL lesions, and the catalytic activity of both these nucleases is essential for ICL repair. As anticipated for a DNA unwinding-independent recognition process, we demonstrate that least distorting ICLs fail to be recognized and repaired by the MMR machinery. This establishes that ICL structure is a critical determinant of repair efficiency outside of DNA replication. Kato et al. identify a mechanism of ICL recognition that operates independently of DNA replication and transcription. In the absence of these processes, ICLs are recognized and repaired by the MMR machinery. MutSα is critical for ICL recognition, while MutLα and EXO1 contribute to key downstream nucleolytic steps during ICL repair.
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影响因子：
16
作者：
Ben-Yehoyada M;Wang LC;Kozekov ID;Rizzo CJ;Gottesman ME;Gautier J
通讯作者：
Gautier J
影响因子：
7.3
作者：
Gregson, SJ;Howard, PW;Thurston, DE
通讯作者：
Thurston, DE
影响因子：
15
作者：
Dooley, PA;Zhang, MZ;Harris, TM
通讯作者：
Harris, TM
影响因子：
4.8
作者：
Genschel, J;Bazemore, LR;Modrich, P
通讯作者：
Modrich, P
影响因子：
4.8
作者：
Dufner, P;Marra, G;Jiricny, J
通讯作者：
Jiricny, J