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

doi:10.1093/nar/gks353

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 journal › Article › peer-review

107 Scopus citations

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 language	English (US)
Pages (from-to)	7347-7357
Number of pages	11
Journal	Nucleic acids research
Volume	40
Issue number	15
DOIs	https://doi.org/10.1093/nar/gks353
State	Published - Aug 2012
Externally published	Yes

ASJC Scopus subject areas

Genetics

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

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.",

author = "Brian Budke and Logan, {Hillary L.} and Kalin, {Jay H.} and Zelivianskaia, {Anna S.} and McGuire, {William Cameron} and Miller, {Luke L.} and Stark, {Jeremy M.} and Kozikowski, {Alan P.} and Bishop, {Douglas K.} and Connell, {Philip P.}",

note = "Funding Information: The National Institutes of Health (NIH) [CA142642-02 2010-2015 to P.P.C., D.K.B., A.P.K., 2T32CA009594 to B.B.]. Funding for open access charge: NIH [CA142642-02].",

year = "2012",

month = aug,

doi = "10.1093/nar/gks353",

language = "English (US)",

volume = "40",

pages = "7347--7357",

journal = "Nucleic acids research",

issn = "0305-1048",

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TY - JOUR

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T2 - A chemical inhibitor of RAD51 that disrupts Homologous recombination in human cells

AU - Budke, Brian

AU - Logan, Hillary L.

AU - Kalin, Jay H.

AU - Zelivianskaia, Anna S.

AU - McGuire, William Cameron

AU - Miller, Luke L.

AU - Stark, Jeremy M.

AU - Kozikowski, Alan P.

AU - Bishop, Douglas K.

AU - Connell, Philip P.

N1 - Funding Information: The National Institutes of Health (NIH) [CA142642-02 2010-2015 to P.P.C., D.K.B., A.P.K., 2T32CA009594 to B.B.]. Funding for open access charge: NIH [CA142642-02].

PY - 2012/8

Y1 - 2012/8

N2 - 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.

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

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