The scaffold protein WRAP53β orchestrates the ubiquitin response critical for DNA double-strand break repair.
The scaffold protein WRAP53β orchestrates the ubiquitin response critical for DNA double-strand break repair.
复制标题
DOI：
10.1101/gad.246546.114
复制
发表时间：
2014-12-15
影响因子：
10.5
通讯作者：
Farnebo M
中科院分区：
文献类型：
--
作者：
Henriksson S;Rassoolzadeh H;Hedström E;Coucoravas C;Julner A;Goldstein M;Imreh G;Zhivotovsky B;Kastan MB;Helleday T;Farnebo M
含有WD 40结构域的蛋白WRAP 53 β控制剪接因子和端粒酶向Cajal小体的运输。在这里，Henriksson等人证明WRAP 53 β以ATM-、H2 AX-和MDC 1-依赖性方式快速定位于双链断裂（DSB）。WRAP 53 β通过促进RNF 8与其上游配偶体MDC 1之间的相互作用来响应DNA损伤，从而将E3连接酶RNF 8靶向DNA损伤。WRAP 53 β的缺失通过同源重组和非同源末端连接损害DSB修复，引起自发DNA断裂的积累，并延迟从辐射诱导的细胞周期停滞中恢复。含有WD 40结构域的蛋白WRAP 53 β（WD 40编码p53反义RNA;也称为WDR 79/TCAB 1）控制剪接因子和端粒酶向卡哈尔体的运输，其功能丧失与致癌作用、过早衰老和神经退行性变有关。在这里，我们确定WRAP 53 β是DNA双链断裂（DSB）修复的重要调节因子。WRAP 53 β以ATM-、H2 AX-和MDC 1-依赖性方式快速定位于DSB。我们发现，WRAP 53 β通过促进RNF 8与其上游伙伴MDC 1之间的相互作用来响应DNA损伤，从而将E3连接酶RNF 8靶向DNA损伤。MDC 1和RNF 8与WRAP 53 β的高度保守的WD 40支架结构域的同时结合促进了它们的相互作用和RNF 8在DSB处的积累。通过这种方式，WRAP 53 β控制DNA损伤位点的适当泛素化以及53 BP 1、BRCA 1和RAD 51的下游组装。此外，我们揭示了WRAP 53 β的敲低通过同源重组（HR）和非同源末端连接（NHEJ）损害DSB修复，导致自发DNA断裂的积累，并延迟从辐射诱导的细胞周期停滞中恢复。我们的研究结果通过为DNA修复因子提供支架，确立了WRAP 53 β作为DSB修复的新型调节因子。
The WD40 domain-containing protein WRAP53β controls trafficking of splicing factors and telomerase to Cajal bodies. Here, Henriksson et al. demonstrate that WRAP53β rapidly localizes to double-strand breaks (DSBs) in an ATM-, H2AX-, and MDC1-dependent manner. WRAP53β targets the E3 ligase RNF8 to DNA lesions by facilitating the interaction between RNF8 and its upstream partner, MDC1, in response to DNA damage. Loss of WRAP53β impairs DSB repair by both homologous recombination and nonhomologous end-joining, causes accumulation of spontaneous DNA breaks, and delays recovery from radiation-induced cell cycle arrest. The WD40 domain-containing protein WRAP53β (WD40 encoding RNA antisense to p53; also referred to as WDR79/TCAB1) controls trafficking of splicing factors and the telomerase enzyme to Cajal bodies, and its functional loss has been linked to carcinogenesis, premature aging, and neurodegeneration. Here, we identify WRAP53β as an essential regulator of DNA double-strand break (DSB) repair. WRAP53β rapidly localizes to DSBs in an ATM-, H2AX-, and MDC1-dependent manner. We show that WRAP53β targets the E3 ligase RNF8 to DNA lesions by facilitating the interaction between RNF8 and its upstream partner, MDC1, in response to DNA damage. Simultaneous binding of MDC1 and RNF8 to the highly conserved WD40 scaffold domain of WRAP53β facilitates their interaction and accumulation of RNF8 at DSBs. In this manner, WRAP53β controls proper ubiquitylation at DNA damage sites and the downstream assembly of 53BP1, BRCA1, and RAD51. Furthermore, we reveal that knockdown of WRAP53β impairs DSB repair by both homologous recombination (HR) and nonhomologous end-joining (NHEJ), causes accumulation of spontaneous DNA breaks, and delays recovery from radiation-induced cell cycle arrest. Our findings establish WRAP53β as a novel regulator of DSB repair by providing a scaffold for DNA repair factors.
登录
查看更多内容
影响因子：
9.8
作者：
Mahmoudi S;Henriksson S;Weibrecht I;Smith S;Söderberg O;Strömblad S;Wiman KG;Farnebo M
通讯作者：
Farnebo M
影响因子：
16
作者：
Paulsen, Renee D.;Soni, Deena V.;Wollman, Roy;Hahn, Angela T.;Yee, Muh-Ching;Guan, Anna;Hesley, Jayne A.;Miller, Steven C.;Cromwell, Evan F.;Solow-Cordero, David E.;Meyer, Tobias;Cimprich, Karlene A.
通讯作者：
Cimprich, Karlene A.
影响因子：
11.4
作者：
Luijsterburg, Martijn S.;Acs, Klara;Dantuma, Nico P.
通讯作者：
Dantuma, Nico P.
影响因子：
9
作者：
通讯作者：
--
DOI：
10.1073/pnas.1306160110
发表时间：
2013-10-15
影响因子：
11.1
作者：
Goldstein, Michael;Derheimer, Frederick A.;Kastan, Michael B.
通讯作者：
Kastan, Michael B.