title: Physical interaction between SLX4 (FANCP) and XPF (FANCQ) proteins and biological consequences of interaction-defective missense mutations.
abstract: SLX4 (FANCP) and XPF (FANCQ) proteins interact with each other and play a vital role in the Fanconi anemia (FA) DNA repair pathway. We have identified a SLX4 region and several amino acid residues that are responsible for this interaction. The study has revealed that the global minor allele, SLX4(Y546C), is defective in this interaction and cannot complement Fancp knockout mouse cells in mitomycin C-induced cytotoxicity or chromosomal aberrations. These results highly suggest this allele, as well as SLX4(L530Q), to be pathogenic. The interacting partner XPF is involved in various DNA repair pathways, and certain XPF mutations cause progeria, Cockayne syndrome (CS), and/or FA phenotypes. Because several atypical xeroderma pigmentosum (XP) phenotype-causing XPF missense mutations are located in the SLX4-interacting region, we suspected the disruption of the interaction with SLX4 in these XPF mutants, thereby causing severer phenotypes. The immunoprecipitation assay of cell extracts revealed that those XPF mutations, except XPF(C236R), located in the SLX4-interacting region cause instability of XPF protein, which could be the reason for the FA, progeria and/or CS phenotypes.
authors.affiliation: Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York, Stony Brook, NY 11794, USA.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Division of Toxicology, Institute of Environmental Toxicology, Ibaraki 303-0043, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Wada
authors.affiliation: Division of Toxicology, Institute of Environmental Toxicology, Ibaraki 303-0043, Japan.
authors.forename: Kyomu
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York, Stony Brook, NY 11794, USA. Electronic address: masaaki.moriya@stonybrook.edu.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Moriya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002869:Chromosome Aberrations / Q000139:chemically induced; D003057:Cockayne Syndrome / Q000235:genetics; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D005816:Genetic Complementation Test; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016685:Mitomycin / Q000494:pharmacology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011371:Progeria / Q000235:genetics; D045522:Recombinases / Q000235:genetics / Q000378:metabolism*; D014983:Xeroderma Pigmentosum / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D045522:Recombinases; C095888:xeroderma pigmentosum group F protein; D016685:Mitomycin; C542319:SLX4 protein, human
keywords: FANCP; Fanconi anemia; Interstrand crosslink repair; Protein–protein interaction; SLX4; XPF