Journal
MOLECULAR CELL
Volume 59, Issue 3, Pages 478-490Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2015.07.009
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Funding
- Starr Center Consortium
- Rita Allen Foundation
- Burroughs Wellcome Foundation
- Irma T. Hirschl Research Award
- Doris Duke Clinical Scientist Development Award
- NIH [GM62653, R01HL120922]
- National Center for Advancing Translational Sciences (NCATS) [8 UL1 TR000043]
- NIH Clinical and Translational Science Award (CTSA) program
- Congressionally Directed Medical Research Programs
- Bone Marrow Failure Research Program Postdoctoral Fellowship Training Award [BM120004]
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Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. In vitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio of mutant to wild-type RAD51 in cells. Instead, patient cells are sensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity.
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