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Nacson J , Krais JJ , Bernhardy AJ , Clausen E , Feng W , Wang Y , Nicolas E , Cai KQ , Tricarico R , Hua X , DiMarcantonio D , Martinez E , Zong D , Handorf EA , Bellacosa A , Testa JR , Nussenzweig A , Gupta GP , Sykes SM , Johnson N
BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance
Cell Rep. 2018 Sep 25;24(13) :3513-3527.e7
PMID: 30257212 PMCID: PMC6219632 URL: https://www.ncbi.nlm.nih.gov/pubmed/30257212
AbstractBRCA1 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(DeltaC/DeltaC) mouse model that harbors a stop codon in the coiled-coil domain. However, Brca1(DeltaC/DeltaC);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.
Notes2211-1247 Nacson, Joseph Krais, John J Bernhardy, Andrea J Clausen, Emma Feng, Wanjuan Wang, Yifan Nicolas, Emmanuelle Cai, Kathy Q Tricarico, Rossella Hua, Xiang DiMarcantonio, Daniela Martinez, Esteban Zong, Dali Handorf, Elizabeth A Bellacosa, Alfonso Testa, Joseph R Nussenzweig, Andre Gupta, Gaorav P Sykes, Stephen M Johnson, Neil Journal Article United States Cell Rep. 2018 Sep 25;24(13):3513-3527.e7. doi: 10.1016/j.celrep.2018.08.086.