ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication.
ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication.
复制标题
atm磷酸化的SPOP有助于在DNA复制期间将53BP1排除在染色质之外。
DOI：
10.1126/sciadv.abd9208
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发表时间：
2021-06
期刊：
影响因子：
13.6
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Wang D;Ma J;Botuyan MV;Cui G;Yan Y;Ding D;Zhou Y;Krueger EW;Pei J;Wu X;Wang L;Pei H;McNiven MA;Ye D;Mer G;Huang H
SPOP突变使53 BP 1不能泛素化，不能从DNA双链断裂位点排除，导致基因组不稳定。53 BP 1激活非同源末端连接（NHEJ）并抑制DNA双链断裂（DSB）的同源重组（HR）修复。53 BP 1从DSB中解离并随后激活HR（一种比NHEJ更不易出错的途径）有助于在DNA复制期间维持基因组完整性;然而，其潜在机制尚未完全了解。在这里，我们证明了E3泛素连接酶SPOP通过从DSB中排除53 BP 1而在细胞周期的S期促进HR。在响应DNA损伤，ATM激酶催化的磷酸化SPOP的原因，在SPOP的构象变化，揭示了X-射线晶体结构，稳定其与53 BP 1的相互作用。53 BP 1结合的SPOP诱导53 BP 1的多聚泛素化，通过含有缬氨素的蛋白质/p97分离酶复合物从染色质中提取53 BP 1。我们的工作表明，在DNA复制过程中，SPOP通过促进53 BP 1从染色质中去除而促进HR修复超过NHEJ。癌症衍生的SPOP突变阻断SPOP与53 BP 1的相互作用，诱导HR缺陷和染色体不稳定性。
SPOP mutation disables 53BP1 ubiquitination and exclusion from DNA double-strand break sites and causes genome instability. 53BP1 activates nonhomologous end joining (NHEJ) and inhibits homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Dissociation of 53BP1 from DSBs and consequent activation of HR, a less error-prone pathway than NHEJ, helps maintain genome integrity during DNA replication; however, the underlying mechanisms are not fully understood. Here, we demonstrate that E3 ubiquitin ligase SPOP promotes HR during S phase of the cell cycle by excluding 53BP1 from DSBs. In response to DNA damage, ATM kinase–catalyzed phosphorylation of SPOP causes a conformational change in SPOP, revealed by x-ray crystal structures, that stabilizes its interaction with 53BP1. 53BP1-bound SPOP induces polyubiquitination of 53BP1, eliciting 53BP1 extraction from chromatin by a valosin-containing protein/p97 segregase complex. Our work shows that SPOP facilitates HR repair over NHEJ during DNA replication by contributing to 53BP1 removal from chromatin. Cancer-derived SPOP mutations block SPOP interaction with 53BP1, inducing HR defects and chromosomal instability.
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影响因子：
14.9
作者：
Hjorth-Jensen K;Maya-Mendoza A;Dalgaard N;Sigurðsson JO;Bartek J;Iglesias-Gato D;Olsen JV;Flores-Morales A
通讯作者：
Flores-Morales A
影响因子：
16.8
作者：
Botuyan MV;Cui G;Drané P;Oliveira C;Detappe A;Brault ME;Parnandi N;Chaubey S;Thompson JR;Bragantini B;Zhao D;Chapman JR;Chowdhury D;Mer G
通讯作者：
Mer G
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4
作者：
Chapman, J. Ross;Sossick, Alex J.;Jackson, Stephen P.
通讯作者：
Jackson, Stephen P.