TY - JOUR
T1 - BRCA1 Mutational Complementation Induces Synthetic Viability
AU - Nacson, Joseph
AU - Di Marcantonio, Daniela
AU - Wang, Yifan
AU - Bernhardy, Andrea J.
AU - Clausen, Emma
AU - Hua, Xiang
AU - Cai, Kathy Q.
AU - Martinez, Esteban
AU - Feng, Wanjuan
AU - Callén, Elsa
AU - Wu, Wei
AU - Gupta, Gaorav P.
AU - Testa, Joseph R.
AU - Nussenzweig, André
AU - Sykes, Stephen M.
AU - Johnson, Neil
N1 - Funding Information:
This work was supported by NIH grants R01CA214799 and R01HL150190 as well as Susan Komen CCRCR17499048 and Department of Defense OC130212. Clovis Oncology supplied rucaparib. We are grateful to the FCCC Genomics, Cell Culture, and Cell Sorting facilities. We thank Dr. Dali Zong for critical reading of the manuscript. We thank Dr. Zemin Liu at the FCCC Cytogenetics facility for help with analyzing metaphase spreads. J.N. D.D.M. Y.W. E.C. A.J.B. W.F. K.Q.C. E.M. W.W. and E.C. designed and performed the experiments. X.H. J.N. and N.J. developed the Brca1CC mouse model. J.N. D.D.M. Y.W. K.Q.C. W.F. G.P.G. J.R.T. A.N. S.M.S. and N.J. analyzed and interpreted the data. J.N. S.M.S. and N.J. wrote the manuscript. N.J. supervised the project. The authors declare no conflicts of interest.
Funding Information:
This work was supported by NIH grants R01CA214799 and R01HL150190 as well as Susan Komen CCRCR17499048 and Department of Defense OC130212 . Clovis Oncology supplied rucaparib. We are grateful to the FCCC Genomics, Cell Culture, and Cell Sorting facilities. We thank Dr. Dali Zong for critical reading of the manuscript. We thank Dr. Zemin Liu at the FCCC Cytogenetics facility for help with analyzing metaphase spreads.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/6/4
Y1 - 2020/6/4
N2 - BRCA1 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 Brca1CC mouse with a coiled-coil (CC) domain deletion. Brca1CC/CC mice are born at low frequencies, and post-natal mice have FA-like abnormalities, including bone marrow failure. Intercrossing with Brca1Δ11, which is homozygous lethal, generated Brca1CC/Δ11 mice at Mendelian frequencies that were indistinguishable from Brca1+/+ mice. Brca1CC and Brca1Δ11 proteins were individually responsible for counteracting 53BP1-RIF1-Shieldin activity and promoting RAD51 loading, respectively. Thus, Brca1CC and Brca1Δ11 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.
AB - BRCA1 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 Brca1CC mouse with a coiled-coil (CC) domain deletion. Brca1CC/CC mice are born at low frequencies, and post-natal mice have FA-like abnormalities, including bone marrow failure. Intercrossing with Brca1Δ11, which is homozygous lethal, generated Brca1CC/Δ11 mice at Mendelian frequencies that were indistinguishable from Brca1+/+ mice. Brca1CC and Brca1Δ11 proteins were individually responsible for counteracting 53BP1-RIF1-Shieldin activity and promoting RAD51 loading, respectively. Thus, Brca1CC and Brca1Δ11 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.
UR - http://www.scopus.com/inward/record.url?scp=85085585240&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2020.04.006
DO - 10.1016/j.molcel.2020.04.006
M3 - Article
C2 - 32359443
AN - SCOPUS:85085585240
SN - 1097-2765
VL - 78
SP - 951-959.e6
JO - Molecular cell
JF - Molecular cell
IS - 5
ER -