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.
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Budke
authors.forename: Hillary L
authors.initials: HL
authors.lastname: Logan
authors.forename: Jay H
authors.initials: JH
authors.lastname: Kalin
authors.forename: Anna S
authors.initials: AS
authors.lastname: Zelivianskaia
authors.forename: William
authors.initials: W
authors.lastname: Cameron McGuire
authors.forename: Luke L
authors.initials: LL
authors.lastname: Miller
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Stark
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Bishop
authors.forename: Philip P
authors.initials: PP
authors.lastname: Connell
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D059765:Homologous Recombination / Q000187:drug effects*; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D021122:Protein Subunits / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: C576134:3-chloro-1-(3,4-dichlorophenyl)-4-(4-morpholinyl)-1H-pyrrole-2,5-dione; D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D009025:Morpholines; D021122:Protein Subunits; D011758:Pyrroles; D016685:Mitomycin; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D003545:Cysteine