RI-1: a Chemical Inhibitor of RAD51 That Disrupts Homologous Recombination in Human Cells

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2012 May 11

PMID 22573178

Citations 102

Authors

Brian Budke

Hillary L Logan

Jay H Kalin

Anna S Zelivianskaia

William Cameron McGuire

Luke L Miller

Jeremy M Stark

Alan P Kozikowski

Douglas K Bishop

Philip P Connell

Affiliations

Soon will be listed here.

Abstract

Homologous recombination serves multiple roles in DNA repair that are essential for maintaining genomic stability. We here describe RI-1, a small molecule that inhibits the central recombination protein RAD51. RI-1 specifically reduces gene conversion in human cells while stimulating single strand annealing. RI-1 binds covalently to the surface of RAD51 protein at cysteine 319 that likely destabilizes an interface used by RAD51 monomers to oligomerize into filaments on DNA. Correspondingly, the molecule inhibits the formation of subnuclear RAD51 foci in cells following DNA damage, while leaving replication protein A focus formation unaffected. Finally, it potentiates the lethal effects of a DNA cross-linking drug in human cells. Given that this inhibitory activity is seen in multiple human tumor cell lines, RI-1 holds promise as an oncologic drug. Furthermore, RI-1 represents a unique tool to dissect the network of reaction pathways that contribute to DNA repair in cells.

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