Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2.
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.
MacKay
Craig
C
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Déclais
Anne-Cécile
AC
Lundin
Cecilia
C
Agostinho
Ana
A
Deans
Andrew J
AJ
MacArtney
Thomas J
TJ
Hofmann
Kay
K
Gartner
Anton
A
West
Stephen C
SC
Helleday
Thomas
T
Lilley
David M J
DM
Rouse
John
J
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
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