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BRCA1 Mutational Complementation Induces Synthetic Viability
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DOI：10.1016/j.molcel.2020.04.006.png)
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摘要
En 中文
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 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(Delta 11), which is homozygous lethal, generated Brca1(CC/Delta 11) mice at Mendelian frequencies that were indistinguishable from Brca1(+/+) mice. Brca1(CC) and Brca1(Delta 11) proteins were individually responsible for counteracting 53BP1-RIF1-Shieldin activity and promoting RAD51 loading, respectively. Thus, Brca1(CC) and Brca1(Delta 11) 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.
Keyword:
HOMOLOGOUS RECOMBINATION
END RESECTION
BRCA1-PALB2 INTERACTION
TUMOR SUPPRESSORS
PARP INHIBITOR
DNA
53BP1
CONNECTS
PATHWAY
DEFECT
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期刊
IF:
16.6
论文数:
1.0W
被引数:
8.5W
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