Format

Send to

Choose Destination
Mol Cell. 2015 Aug 6;59(3):478-90. doi: 10.1016/j.molcel.2015.07.009.

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

Author information

1
Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA.
2
Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA 95616, USA.
3
Blood and Marrow Transplant Program, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
4
Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
5
New York Genome Center, New York, NY 10013, USA.
6
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
7
Human Genetics and Hematology, The Rockefeller University, New York, NY 10065, USA.
8
Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA. Electronic address: asmogorzewska@rockefeller.edu.

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.

PMID:
26253028
PMCID:
PMC4529964
DOI:
10.1016/j.molcel.2015.07.009
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center