BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance
Summary: 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 fou...
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2018-09-01
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doaj-15906ffa1f7e4720aad5040b5000ade92020-11-24T21:47:39ZengElsevierCell Reports2211-12472018-09-01241335133527.e7BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor ResistanceJoseph Nacson0John J. Krais1Andrea J. Bernhardy2Emma Clausen3Wanjuan Feng4Yifan Wang5Emmanuelle Nicolas6Kathy Q. Cai7Rossella Tricarico8Xiang Hua9Daniela DiMarcantonio10Esteban Martinez11Dali Zong12Elizabeth A. Handorf13Alfonso Bellacosa14Joseph R. Testa15Andre Nussenzweig16Gaorav P. Gupta17Stephen M. Sykes18Neil Johnson19Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Temple University, Lewis Katz School of Medicine, Philadelphia, PA 19140, USAMolecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USAMolecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USAMolecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USADepartment of Radiation Oncology, UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USAMolecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USAMolecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Genomics Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USAHistopathology Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USABlood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USABlood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USABlood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USALaboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20892, USABiostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USALaboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20892, USADepartment of Radiation Oncology, UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USABlood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USAMolecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Corresponding authorSummary: 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. : Using a Brca1ΔC mouse model and a panel of BRCA1 mutant cancer cell lines, Nacson et al. show that 53BP1 loss of function induced homologous recombination and PARP inhibitor resistance is suboptimal in the absence of hypomorphic BRCA1 proteins that retain the coiled-coil domain and ability to interact with PALB2. Keywords: BRCA1, 53BP1, homologous recombination, PARP inhibitors, resistancehttp://www.sciencedirect.com/science/article/pii/S2211124718314050 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Joseph Nacson John J. Krais Andrea J. Bernhardy Emma Clausen Wanjuan Feng Yifan Wang Emmanuelle Nicolas Kathy Q. Cai Rossella Tricarico Xiang Hua Daniela DiMarcantonio Esteban Martinez Dali Zong Elizabeth A. Handorf Alfonso Bellacosa Joseph R. Testa Andre Nussenzweig Gaorav P. Gupta Stephen M. Sykes Neil Johnson |
spellingShingle |
Joseph Nacson John J. Krais Andrea J. Bernhardy Emma Clausen Wanjuan Feng Yifan Wang Emmanuelle Nicolas Kathy Q. Cai Rossella Tricarico Xiang Hua Daniela DiMarcantonio Esteban Martinez Dali Zong Elizabeth A. Handorf Alfonso Bellacosa Joseph R. Testa Andre Nussenzweig Gaorav P. Gupta Stephen M. Sykes Neil Johnson BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance Cell Reports |
author_facet |
Joseph Nacson John J. Krais Andrea J. Bernhardy Emma Clausen Wanjuan Feng Yifan Wang Emmanuelle Nicolas Kathy Q. Cai Rossella Tricarico Xiang Hua Daniela DiMarcantonio Esteban Martinez Dali Zong Elizabeth A. Handorf Alfonso Bellacosa Joseph R. Testa Andre Nussenzweig Gaorav P. Gupta Stephen M. Sykes Neil Johnson |
author_sort |
Joseph Nacson |
title |
BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance |
title_short |
BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance |
title_full |
BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance |
title_fullStr |
BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance |
title_full_unstemmed |
BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance |
title_sort |
brca1 mutation-specific responses to 53bp1 loss-induced homologous recombination and parp inhibitor resistance |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2018-09-01 |
description |
Summary: 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. : Using a Brca1ΔC mouse model and a panel of BRCA1 mutant cancer cell lines, Nacson et al. show that 53BP1 loss of function induced homologous recombination and PARP inhibitor resistance is suboptimal in the absence of hypomorphic BRCA1 proteins that retain the coiled-coil domain and ability to interact with PALB2. Keywords: BRCA1, 53BP1, homologous recombination, PARP inhibitors, resistance |
url |
http://www.sciencedirect.com/science/article/pii/S2211124718314050 |
work_keys_str_mv |
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