Ring Finger Nuclear Factor RNF168 Is Important for Defects in Homologous Recombination Caused by Loss of the Breast Cancer Susceptibility Factor BRCA1
Ring Finger Nuclear Factor RNF168 Is Important for Defects in Homologous Recombination Caused by Loss of the Breast Cancer Susceptibility Factor BRCA1
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DOI：
10.1074/jbc.m112.410951
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发表时间：
2012-11-23
影响因子：
4.8
通讯作者：
Stark, Jeremy M.
中科院分区：
文献类型：
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作者：
Munoz, Meilen C.;Laulier, Corentin;Stark, Jeremy M.
包括53BP1和BRCA1在内的几种DNA损伤反应因子双链断裂（dsb）的招募需要环指核因子RNF168。由于53BP1和BRCA1在DSB修复通路同源重组（HR）中起拮抗作用，RNF168对HR的影响尚不清楚。我们报道RNF168缺失导致两种不同的HR通路（同源定向修复和单链退火）频率升高，抑制由BRCA1沉默引起的HR缺陷，但不抑制由CtIP、RAD50、BRCA2或RAD51中断引起的HR缺陷。此外，rnf168缺失的细胞可以形成电离辐射诱导的重组酶RAD51的病灶，而不会形成BRCA1电离辐射诱导的病灶，这表明BRCA1向dsb募集的丧失并不反映HR期间功能的丧失。此外，我们发现RNF168和53BP1对HR有相似的影响。我们认为RNF168对于BRCA1缺失引起的HR缺陷很重要。
The RING finger nuclear factor RNF168 is required for recruitment of several DNA damage response factors to double strand breaks (DSBs), including 53BP1 and BRCA1. Because 53BP1 and BRCA1 function antagonistically during the DSB repair pathway homologous recombination (HR), the influence of RNF168 on HR has been unclear. We report that RNF168 depletion causes an elevated frequency of two distinct HR pathways (homology-directed repair and single strand annealing), suppresses defects in HR caused by BRCA1 silencing, but does not suppress HR defects caused by disruption of CtIP, RAD50, BRCA2, or RAD51. Furthermore, RNF168-depleted cells can form ionizing radiation-induced foci of the recombinase RAD51 without forming BRCA1 ionizing radiation-induced foci, indicating that this loss of BRCA1 recruitment to DSBs does not reflect a loss of function during HR. Additionally, we find that RNF168 and 53BP1 have a similar influence on HR. We suggest that RNF168 is important for HR defects caused by BRCA1 loss.