This is an archive of papers published by the staff and faculty of Fox Chase Cancer Center. For questions about content, please contact Talbot Research Library
Last updated on
Nacson J , Di Marcantonio D , Wang Y , Bernhardy AJ , Clausen E , Hua X , Cai KQ , Martinez E , Feng W , Callen E , Wu W , Gupta GP , Testa JR , Nussenzweig A , Sykes SM , Johnson N
BRCA1 Mutational Complementation Induces Synthetic Viability
Mol Cell. 2020 Jun 4;78(5) :951-959 e6
PMID: 32359443 PMCID: PMC7418109 URL: https://www.ncbi.nlm.nih.gov/pubmed/32359443
AbstractBRCA1 promotes the DNA end resection and RAD51 loading steps of homologous recombination (HR). Whether these functions can be uncoupled, and whether mutant proteins retaining partial activity can complement one another, is unclear and could affect the severity of BRCA1-associated Fanconi anemia (FA). Here we generated a Brca1(CC) mouse with a coiled-coil (CC) domain deletion. Brca1(CC/CC) mice are born at low frequencies, and post-natal mice have FA-like abnormalities, including bone marrow failure. Intercrossing with Brca1(Delta11), which is homozygous lethal, generated Brca1(CC/Delta11) mice at Mendelian frequencies that were indistinguishable from Brca1(+/+) mice. Brca1(CC) and Brca1(Delta11) proteins were individually responsible for counteracting 53BP1-RIF1-Shieldin activity and promoting RAD51 loading, respectively. Thus, Brca1(CC) and Brca1(Delta11) alleles represent separation-of-function mutations that combine to provide a level of HR sufficient for normal development and hematopoiesis. Because BRCA1 activities can be genetically separated, compound heterozygosity for functional complementary mutations may protect individuals from FA.
Notes1097-4164 Nacson, Joseph Di Marcantonio, Daniela Wang, Yifan Bernhardy, Andrea J Clausen, Emma Hua, Xiang Cai, Kathy Q Martinez, Esteban Feng, Wanjuan Callen, Elsa Wu, Wei Gupta, Gaorav P Testa, Joseph R Nussenzweig, Andre Sykes, Stephen M Johnson, Neil Journal Article United States Mol Cell. 2020 Apr 30. pii: S1097-2765(20)30232-X. doi: 10.1016/j.molcel.2020.04.006.