A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination.
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Abstract | 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. |
Year of Publication | 2015
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Journal | Mol Cell
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Volume | 59
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Issue | 3
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Pages | 478-90
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Date Published | 2015 Aug 06
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ISSN | 1097-4164
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URL | |
DOI | 10.1016/j.molcel.2015.07.009
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PubMed ID | 26253028
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PubMed Central ID | PMC4529964
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Grant list | UL1 TR000043 / TR / NCATS NIH HHS / United States
T32 GM066699 / GM / NIGMS NIH HHS / United States
R01 HL120922 / HL / NHLBI NIH HHS / United States
R37 GM062653 / GM / NIGMS NIH HHS / United States
R01 GM062653 / GM / NIGMS NIH HHS / United States
GM62653 / GM / NIGMS NIH HHS / United States
8 UL1 TR000043 / TR / NCATS NIH HHS / United States
R01HL120922 / HL / NHLBI NIH HHS / United States
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