BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance
BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance
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DOI：
10.1016/j.celrep.2018.08.086
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发表时间：
2018-09-25
期刊：
影响因子：
8.8
通讯作者：
Johnson, Neil
中科院分区：
文献类型：
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作者：
Nacson, Joseph;Krais, John J.;Johnson, Neil
BRCA1 在 DNA 末端切除的上游和下游的同源重组 (HR) 中发挥作用。然而，在53BP1基因敲除（KO）的细胞中，BRCA1对于开始切除来说是可有可无的，但在末端切除后BRCA1活性是否完全多余尚不清楚。在这里，我们发现 53bp1 KO 挽救了卷曲螺旋结构域中含有终止密码子的 Brca1(Delta C/Delta C) 小鼠模型的胚胎活力。然而，Brca1(Delta C/Delta C)； 53bp1(-/-) 小鼠容易形成肿瘤，缺乏 Rad51 灶，并且对 PARP 抑制剂 (PARPi) 治疗敏感，表明 HR 不理想。此外，BRCA1 突变癌细胞系依赖于截短的 BRCA1 蛋白，这些蛋白保留了与 PALB2 相互作用的能力，从而实现 53BP1 KO 诱导的 RAD51 病灶和 PARPi 耐药性。我们的数据表明，53BP1 功能丧失诱导 HR 的总体效率可能依赖于 BRCA1 突变。在 53BP1 KO 的情况下，亚形性 BRCA1 蛋白在末端切除下游活跃，促进 RAD51 负载和 PARPi 耐药。
BRCA1 functions in homologous recombination (HR) both up-and downstream of DNA end resection. However, in cells with 53BP1 gene knockout (KO), BRCA1 is dispensable for the initiation of resection, but whether BRCA1 activity is entirely redundant after end resection is unclear. Here, we found that 53bp1 KO rescued the embryonic viability of a Brca1(Delta C/Delta C) mouse model that harbors a stop codon in the coiled-coil domain. However, Brca1(Delta C/Delta C); 53bp1(-/-) mice were susceptible to tumor formation, lacked Rad51 foci, and were sensitive to PARP inhibitor (PARPi) treatment, indicative of suboptimal HR. Furthermore, BRCA1 mutant cancer cell lines were dependent on truncated BRCA1 proteins that retained the ability to interact with PALB2 for 53BP1 KO induced RAD51 foci and PARPi resistance. Our data suggest that the overall efficiency of 53BP1 loss of function induced HR may be BRCA1 mutation dependent. In the setting of 53BP1 KO, hypomorphic BRCA1 proteins are active downstream of end resection, promoting RAD51 loading and PARPi resistance.