Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of Brca2 and Stable Rad51 Nucleofilaments.
Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of Brca2 and Stable Rad51 Nucleofilaments.
复制标题
DOI：
10.1016/j.molcel.2017.07.001
复制
发表时间：
2017-09-07
期刊：
影响因子：
16
通讯作者：
Costanzo V
中科院分区：
文献类型：
--
作者：
Kolinjivadi AM;Sannino V;De Antoni A;Zadorozhny K;Kilkenny M;Técher H;Baldi G;Shen R;Ciccia A;Pellegrini L;Krejci L;Costanzo V
Brca 2缺陷导致Mre 11依赖性降解的新生DNA在停滞的叉，导致细胞死亡。为了了解这一过程的分子机制，我们分离出非洲爪蟾Brca 2。我们证明了Brca 2蛋白通过促进Rad 51与复制DNA的结合来防止复制叉连接处及其后面的单链DNA缺口积累。如果没有Brca 2，Smarcal 1会将具有持久缺口的分叉转化为反向分叉，从而引发广泛的Mre 11依赖性新生DNA降解。稳定的Rad 51核丝，而不是RPA或Rad 51 T131 P突变蛋白，直接阻止Mre 11依赖的DNA降解。相反，在不存在Brca 2的情况下，Mre 11抑制促进反向叉积累。Rad 51直接与Pol α N-末端结构域相互作用，促进Pol α和δ与停滞的复制叉结合。这种交互可能会促进复制分叉的重新启动和间隙避免。这些结果表明，Brca 2和Rad 51防止形成异常的DNA复制中间体，其处理由Smarcal 1和Mre 11倾向于基因组的不稳定性。Brca 2促进Rad 51与复制DNA结合，防止分叉缺口稳定的Rad 51核丝直接保护DNA免受Mre 11依赖性降解Smarcal 1依赖性分叉逆转触发广泛的Mre 11依赖性DNA降解Rad 51直接与Pol α相互作用，促进其在停滞分叉处的功能。显示Brca 2通过促进Rad 51与复制DNA的结合来保护复制叉。然后Rad 51直接与Pol α相互作用，抑制复制过程中ssDNA缺口的出现。当叉停滞时，Brca 2依赖性Rad 51核丝的形成会阻止Smarcal 1介导的叉逆转引发的广泛的Mre 11依赖性新生DNA降解。
Brca2 deficiency causes Mre11-dependent degradation of nascent DNA at stalled forks, leading to cell lethality. To understand the molecular mechanisms underlying this process, we isolated Xenopus laevis Brca2. We demonstrated that Brca2 protein prevents single-stranded DNA gap accumulation at replication fork junctions and behind them by promoting Rad51 binding to replicating DNA. Without Brca2, forks with persistent gaps are converted by Smarcal1 into reversed forks, triggering extensive Mre11-dependent nascent DNA degradation. Stable Rad51 nucleofilaments, but not RPA or Rad51T131P mutant proteins, directly prevent Mre11-dependent DNA degradation. Mre11 inhibition instead promotes reversed fork accumulation in the absence of Brca2. Rad51 directly interacts with the Pol α N-terminal domain, promoting Pol α and δ binding to stalled replication forks. This interaction likely promotes replication fork restart and gap avoidance. These results indicate that Brca2 and Rad51 prevent formation of abnormal DNA replication intermediates, whose processing by Smarcal1 and Mre11 predisposes to genome instability. Brca2 promotes Rad51 binding to replicating DNA, preventing fork gaps Stable Rad51 nucleofilaments directly protect DNA from Mre11-dependent degradation Smarcal1-dependent fork reversal triggers extensive Mre11-dependent DNA degradation Rad51 directly interacts with Pol α, promoting its function at stalled forks Kolinjivadi et al. show that Brca2 protects replication forks by promoting Rad51 binding to replicating DNA. Rad51 then directly interacts with Pol α, suppressing the occurrence of ssDNA gaps during replication. When forks stall, Brca2-dependent Rad51 nucleofilament formation prevents extensive Mre11-dependent nascent DNA degradation triggered by Smarcal1-mediated fork reversal.
登录
查看更多内容
影响因子：
13.8
作者：
Flynn, Rachel Litman;Zou, Lee
通讯作者：
Zou, Lee
影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
8.8
作者：
Bétous R;Couch FB;Mason AC;Eichman BF;Manosas M;Cortez D
通讯作者：
Cortez D
影响因子：
16
作者：
Costanzo, V;Robertson, K;Gautier, J
通讯作者：
Gautier, J
DOI：
10.1007/978-1-61779-129-1_25
发表时间：
2011-01-01
期刊：
DNA RECOMBINATION: METHODS AND PROTOCOLS
影响因子：
--
作者：
Hashimoto, Yoshitami;Costanzo, Vincenzo
通讯作者：
Costanzo, Vincenzo