Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents.
Cytotoxicity of cisplatin and mitomycin C (MMC) is ascribed largely to their ability to generate interstrand crosslinks (ICLs) in DNA, which block the progression of replication forks. The processing of ICLs requires the Fanconi anemia (FA) pathway, excision repair, and translesion DNA synthesis (TLS). It also requires homologous recombination (HR), which repairs double-strand breaks (DSBs) generated by cleavage of the blocked replication forks. Here we describe KIAA1018, an evolutionarily conserved protein that has an N-terminal ubiquitin-binding zinc finger (UBZ) and a C-terminal nuclease domain. KIAA1018 is a 5'-->3' exonuclease and a structure-specific endonuclease that preferentially incises 5' flaps. Like cells from FA patients, human cells depleted of KIAA1018 are sensitized to ICL-inducing agents and display chromosomal instability. The link of KIAA1018 to the FA pathway is further strengthened by its recruitment to DNA damage through interaction of its UBZ domain with monoubiquitylated FANCD2. We therefore propose to name KIAA1018 FANCD2-associated nuclease, FAN1.
Kratz
Katja
K
Institute of Molecular Cancer Research, University of Zurich, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Schöpf
Barbara
B
Kaden
Svenja
S
Sendoel
Ataman
A
Eberhard
Ralf
R
Lademann
Claudio
C
Cannavó
Elda
E
Sartori
Alessandro A
AA
Hengartner
Michael O
MO
Jiricny
Josef
J
D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D004706:Endodeoxyribonucleases; D004720:Endonucleases / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000737:chemistry / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology*; D008969:Molecular Sequence Data; D064251:Multifunctional Enzymes; D043264:Phosphodiesterase I / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D003432:Cross-Linking Reagents; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D064251:Multifunctional Enzymes; D016685:Mitomycin; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005090:Exodeoxyribonucleases; C551063:FAN1 protein, human; D043264:Phosphodiesterase I