RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination.
RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination.
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DOI：
10.1038/onc.2012.391
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发表时间：
2013-07-25
期刊：
影响因子：
8
通讯作者：
Powell SN
中科院分区：
文献类型：
--
作者：
Lok BH;Carley AC;Tchang B;Powell SN
综合致死率是一种研究基于基因型的选择性细胞杀伤的方法。我们实验室以前的工作表明，在BRCA 2缺陷的情况下，RAD 52的缺失是合成致死的，同时对BRCA 2-proficient细胞的细胞生长和活力没有影响。我们现在表明，这种相同的合成致死关系在BRCA 1或PALB 2缺陷的细胞中是明显的，这意味着BRCA 1，PALB 2和BRCA 2彼此之间存在上位关系。当在BRCA 1或PALB 2缺陷细胞中耗尽RAD 52时，观察到平板接种效率严重降低，在双重耗尽的背景中明显存在许多细胞分裂的失败尝试。相反，当在BRCA 1-或PALB 2-野生型背景中耗尽RAD 52时，观察到集落存活率的可忽略的降低。电离辐射诱导的RAD 51灶形成和双链断裂诱导的同源重组（HR）的频率分别降低了3倍和10倍，当RAD 52在BRCA 1或PALB 2缺失细胞中被敲低时，对BRCA 1或PALB 2熟练细胞的影响最小。RAD 52功能独立于BRCA 1状态，这可以通过BRCA 1缺失细胞中RAD 52灶形成缺乏任何缺陷来证明。总的来说，这些发现表明，RAD 52是RAD 51介导的HR的替代修复途径，并且是BRCA 1-PALB 2-BRCA 2修复途径缺陷细胞的治疗靶点。
Synthetic lethality is an approach to study selective cell killing based on genotype. Previous work in our laboratory has shown that loss of RAD52 is synthetically lethal with BRCA2 deficiency, while exhibiting no impact on cell growth and viability in BRCA2-proficient cells. We now show that this same synthetically lethal relationship is evident in cells with deficiencies in BRCA1 or PALB2, which implicates BRCA1, PALB2 and BRCA2 in an epistatic relationship with one another. When RAD52 was depleted in BRCA1- or PALB2-deficient cells, a severe reduction in plating efficiency was observed, with many abortive attempts at cell division apparent in the double-depleted background. In contrast, when RAD52 was depleted in a BRCA1- or PALB2-wildtype background, a negligible decrease in colony survival was observed. The frequency of ionizing radiation-induced RAD51 foci formation and double-strand break-induced homologous recombination (HR) was decreased by 3- and 10-fold, respectively, when RAD52 was knocked down in BRCA1- or PALB2-depleted cells, with minimal effect in BRCA1- or PALB2-proficient cells. RAD52 function was independent of BRCA1 status, as evidenced by the lack of any defect in RAD52 foci formation in BRCA1-depleted cells. Collectively, these findings suggest that RAD52 is an alternative repair pathway of RAD51-mediated HR, and a target for therapy in cells deficient in the BRCA1– PALB2–BRCA2 repair pathway.
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120.1
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