RI-1: A chemical inhibitor of RAD51 that disrupts Homologous recombination in human cells

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)7347-7357
Number of pages11
JournalNucleic acids research
Volume40
Issue number15
DOIs
StatePublished - Aug 1 2012

ASJC Scopus subject areas

  • Genetics

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    Budke, B., Logan, H. L., Kalin, J. H., Zelivianskaia, A. S., McGuire, W. C., Miller, L. L., Stark, J. M., Kozikowski, A. P., Bishop, D. K., & Connell, P. P. (2012). RI-1: A chemical inhibitor of RAD51 that disrupts Homologous recombination in human cells. Nucleic acids research, 40(15), 7347-7357. https://doi.org/10.1093/nar/gks353