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A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination.

Authors
  • At, Wang
  • Taeho Kim
  • Je, Wagner
  • Ba, Conti
  • Fp, Lach
  • Al, Huang
  • H, Molina
  • Em, Sanborn
  • H, Zierhut
  • Bk, Cornes
  • A, Abhyankar
  • C, Sougnez
  • Sb, Gabriel
  • Ad, Auerbach
  • Stephen Charles Kowalczykowski
  • A, Smogorzewska
Type
Published Article
Journal
Molecular Cell
Publisher
Elsevier
Volume
59
Issue
3
Pages
478–490
Identifiers
DOI: 10.1016/j.molcel.2015.07.009
Source
Kowalczykowski Lab
License
Unknown

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.

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