title: Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2.
abstract: DNA interstrand crosslinks (ICLs) are highly toxic because they block the progression of replisomes. The Fanconi Anemia (FA) proteins, encoded by genes that are mutated in FA, are important for repair of ICLs. The FA core complex catalyzes the monoubiquitination of FANCD2, and this event is essential for several steps of ICL repair. However, how monoubiquitination of FANCD2 promotes ICL repair at the molecular level is unknown. Here, we describe a highly conserved protein, KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2. FAN1 exhibits endonuclease activity toward 5' flaps and has 5' exonuclease activity, and these activities are mediated by an ancient VRR_nuc domain. Depletion of FAN1 from human cells causes hypersensitivity to ICLs, defects in ICL repair, and genome instability. These data at least partly explain how ubiquitination of FANCD2 promotes DNA repair.
authors.affiliation: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: MacKay
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Déclais
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lundin
authors.forename: Ana
authors.initials: A
authors.lastname: Agostinho
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Deans
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: MacArtney
authors.forename: Kay
authors.initials: K
authors.lastname: Hofmann
authors.forename: Anton
authors.initials: A
authors.lastname: Gartner
authors.forename: Stephen C
authors.initials: SC
authors.lastname: West
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.forename: David M J
authors.initials: DM
authors.lastname: Lilley
authors.forename: John
authors.initials: J
authors.lastname: Rouse
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D024682:BRCA2 Protein / Q000378:metabolism; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D004706:Endodeoxyribonucleases; D004720:Endonucleases / Q000737:chemistry / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000737:chemistry / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D064251:Multifunctional Enzymes; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D054875:Ubiquitination
chemical_list: D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D003432:Cross-Linking Reagents; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D064251:Multifunctional Enzymes; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005090:Exodeoxyribonucleases; C551063:FAN1 protein, human