title: Regulation of multiple DNA repair pathways by the Fanconi anemia protein SLX4.
abstract: SLX4, the newly identified Fanconi anemia protein, FANCP, is implicated in repairing DNA damage induced by DNA interstrand cross-linking (ICL) agents, topoisomerase I (TOP1) inhibitors, and in Holliday junction resolution. It interacts with and enhances the activity of XPF-ERCC1, MUS81-EME1, and SLX1 nucleases, but the requirement for the specific nucleases in SLX4 function is unclear. Here, by complementing a null FA-P Fanconi anemia cell line with SLX4 mutants that specifically lack the interaction with each of the nucleases, we show that the SLX4-dependent XPF-ERCC1 activity is essential for ICL repair but is dispensable for repairing TOP1 inhibitor-induced DNA lesions. Conversely, MUS81-SLX4 interaction is critical for resistance to TOP1 inhibitors but is less important for ICL repair. Mutation of SLX4 that abrogates interaction with SLX1 results in partial resistance to both cross-linking agents and TOP1 inhibitors. These results demonstrate that SLX4 modulates multiple DNA repair pathways by regulating appropriate nucleases.
authors.affiliation: Laboratory of Genome Maintenance, Rockefeller University, New York, NY 10065-6399, USA.
authors.forename: Yonghwan
authors.initials: Y
authors.lastname: Kim
authors.forename: Gabriella S
authors.initials: GS
authors.lastname: Spitz
authors.forename: Uma
authors.initials: U
authors.lastname: Veturi
authors.forename: Francis P
authors.initials: FP
authors.lastname: Lach
authors.forename: Arleen D
authors.initials: AD
authors.lastname: Auerbach
authors.forename: Agata
authors.initials: A
authors.lastname: Smogorzewska
mesh_terms: D002166:Camptothecin / Q000633:toxicity; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000633:toxicity; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000502:physiology*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases; D004720:Endonucleases / Q000378:metabolism; D005199:Fanconi Anemia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D016685:Mitomycin / Q000633:toxicity; D010793:Phthalazines / Q000633:toxicity; D010879:Piperazines / Q000633:toxicity; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D045522:Recombinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D059004:Topoisomerase I Inhibitors / Q000633:toxicity
chemical_list: D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011993:Recombinant Fusion Proteins; D045522:Recombinases; D059004:Topoisomerase I Inhibitors; C095888:xeroderma pigmentosum group F protein; D016685:Mitomycin; D004247:DNA; D004706:Endodeoxyribonucleases; D004720:Endonucleases; C498772:MUS81 protein, human; C542320:SLX1 protein, human; C542319:SLX4 protein, human; D045643:DNA Repair Enzymes; C531550:olaparib; D002166:Camptothecin