BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance

著者: Joseph Nacson, John J. Krais, Andrea J. Bernhardy, Emma Clausen, Wanjuan Feng, Yifan Wang, Émmanuelle Nicolas, Kathy Q. Cai, Rossella Tricarico, Hua Xiang, Daniela Di Marcantonio, Esteban Martı́nez, Dali Zong, Elizabeth A. Handorf, Alfonso Bellacosa, Joseph R. Testa, André Nussenzweig, Gaorav P. Gupta, Stephen M. Sykes, Neil Johnson - Cell Reports 2018 被引用: 98

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.