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BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance.
Cell Reports ( IF 7.5 ) Pub Date : 2018-09-25 , DOI: 10.1016/j.celrep.2018.08.086
Joseph Nacson 1 , John J Krais 2 , Andrea J Bernhardy 2 , Emma Clausen 2 , Wanjuan Feng 3 , Yifan Wang 2 , Emmanuelle Nicolas 4 , Kathy Q Cai 5 , Rossella Tricarico 6 , Xiang Hua 7 , Daniela DiMarcantonio 7 , Esteban Martinez 7 , Dali Zong 8 , Elizabeth A Handorf 9 , Alfonso Bellacosa 6 , Joseph R Testa 10 , Andre Nussenzweig 8 , Gaorav P Gupta 3 , Stephen M Sykes 7 , Neil Johnson 2
Cell Reports ( IF 7.5 ) Pub Date : 2018-09-25 , DOI: 10.1016/j.celrep.2018.08.086
Joseph Nacson 1 , John J Krais 2 , Andrea J Bernhardy 2 , Emma Clausen 2 , Wanjuan Feng 3 , Yifan Wang 2 , Emmanuelle Nicolas 4 , Kathy Q Cai 5 , Rossella Tricarico 6 , Xiang Hua 7 , Daniela DiMarcantonio 7 , Esteban Martinez 7 , Dali Zong 8 , Elizabeth A Handorf 9 , Alfonso Bellacosa 6 , Joseph R Testa 10 , Andre Nussenzweig 8 , Gaorav P Gupta 3 , Stephen M Sykes 7 , Neil Johnson 2
Affiliation
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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 Brca1ΔC/ΔC mouse model that harbors a stop codon in the coiled-coil domain. However, Brca1ΔC/ΔC;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.
中文翻译：
对53BP1损失诱导的同源重组和PARP抑制剂抗性的BRCA1突变特异性反应。
BRCA1在DNA末端切除术的上游和下游均在同源重组（HR）中起作用。然而，在具有53BP1基因敲除（KO）的细胞中，BRCA1对于开始切除是必不可少的，但不清楚末端切除后BRCA1活性是否完全多余。在这里，我们发现53bp1 KO拯救了在卷曲螺旋结构域中带有终止密码子的Brca1ΔC/ΔC小鼠模型的胚胎生存能力。然而，Brca1ΔC/ΔC; 53bp1-/-小鼠对肿瘤形成敏感，缺乏Rad51病灶，并且对PARP抑制剂（PARPi）治疗敏感，表明HR欠佳。此外，BRCA1突变癌细胞系依赖于截短的BRCA1蛋白，该蛋白保留了与PALB2相互作用的能力，可用于53BP1 KO诱导的RAD51病灶和PARPi抗性。我们的数据表明53BP1功能丧失引起的HR的整体效率可能与BRCA1突变有关。在53BP1 KO的情况下，亚型BRCA1蛋白在末端切除的下游起作用，从而促进RAD51加载和PARPi抗性。
更新日期：2018-09-26
中文翻译：
对53BP1损失诱导的同源重组和PARP抑制剂抗性的BRCA1突变特异性反应。
BRCA1在DNA末端切除术的上游和下游均在同源重组（HR）中起作用。然而，在具有53BP1基因敲除（KO）的细胞中，BRCA1对于开始切除是必不可少的，但不清楚末端切除后BRCA1活性是否完全多余。在这里，我们发现53bp1 KO拯救了在卷曲螺旋结构域中带有终止密码子的Brca1ΔC/ΔC小鼠模型的胚胎生存能力。然而，Brca1ΔC/ΔC; 53bp1-/-小鼠对肿瘤形成敏感，缺乏Rad51病灶，并且对PARP抑制剂（PARPi）治疗敏感，表明HR欠佳。此外，BRCA1突变癌细胞系依赖于截短的BRCA1蛋白，该蛋白保留了与PALB2相互作用的能力，可用于53BP1 KO诱导的RAD51病灶和PARPi抗性。我们的数据表明53BP1功能丧失引起的HR的整体效率可能与BRCA1突变有关。在53BP1 KO的情况下，亚型BRCA1蛋白在末端切除的下游起作用，从而促进RAD51加载和PARPi抗性。
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