Format

Send to

Choose Destination
Nucleic Acids Res. 2015 Jan;43(2):1098-111. doi: 10.1093/nar/gku1337. Epub 2014 Dec 24.

Tumor-associated mutations in a conserved structural motif alter physical and biochemical properties of human RAD51 recombinase.

Author information

1
Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, USA.
2
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Radiation Oncology, University of California-Los Angeles, Los Angeles, CA 90095, USA.
4
Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT 05405, USA Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
5
Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT 05405, USA.
6
Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, USA Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT 05405, USA smorrica@uvm.edu.

Abstract

Human RAD51 protein catalyzes DNA pairing and strand exchange reactions that are central to homologous recombination and homology-directed DNA repair. Successful recombination/repair requires the formation of a presynaptic filament of RAD51 on ssDNA. Mutations in BRCA2 and other proteins that control RAD51 activity are associated with human cancer. Here we describe a set of mutations associated with human breast tumors that occur in a common structural motif of RAD51. Tumor-associated D149N, R150Q and G151D mutations map to a Schellman loop motif located on the surface of the RecA homology domain of RAD51. All three variants are proficient in DNA strand exchange, but G151D is slightly more sensitive to salt than wild-type (WT). Both G151D and R150Q exhibit markedly lower catalytic efficiency for adenosine triphosphate hydrolysis compared to WT. All three mutations alter the physical properties of RAD51 nucleoprotein filaments, with G151D showing the most dramatic changes. G151D forms mixed nucleoprotein filaments with WT RAD51 that have intermediate properties compared to unmixed filaments. These findings raise the possibility that mutations in RAD51 itself may contribute to genome instability in tumor cells, either directly through changes in recombinase properties, or indirectly through changes in interactions with regulatory proteins.

PMID:
25539919
PMCID:
PMC4333388
DOI:
10.1093/nar/gku1337
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center