Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM.
The Fanconi anemia (FA) core complex plays a crucial role in a DNA damage response network with BRCA1 and BRCA2. How this complex interacts with damaged DNA is unknown, as only the FA core protein FANCM (the homolog of an archaeal helicase/nuclease known as HEF) exhibits DNA binding activity. Here, we describe the identification of FAAP24, a protein that targets FANCM to structures that mimic intermediates formed during the replication/repair of damaged DNA. FAAP24 shares homology with the XPF family of flap/fork endonucleases, associates with the C-terminal region of FANCM, and is a component of the FA core complex. FAAP24 is required for normal levels of FANCD2 monoubiquitylation following DNA damage. Depletion of FAAP24 by siRNA results in cellular hypersensitivity to DNA crosslinking agents and chromosomal instability. Our data indicate that the FANCM/FAAP24 complex may play a key role in recruitment of the FA core complex to damaged DNA.
Ciccia
Alberto
A
Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Herts, UK.
Ling
Chen
C
Coulthard
Rachel
R
Yan
Zhijiang
Z
Xue
Yutong
Y
Meetei
Amom Ruhikanta
AR
Laghmani
El Houari
el H
Joenje
Hans
H
McDonald
Neil
N
de Winter
Johan P
JP
Wang
Weidong
W
West
Stephen C
SC
D000595:Amino Acid Sequence; D004249:DNA Damage; D004265:DNA Helicases / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D004261:DNA Replication / Q000502:physiology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D051856:Fanconi Anemia Complementation Group Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; C518296:FAAP24 protein, human; D051856:Fanconi Anemia Complementation Group Proteins; D025801:Ubiquitin; C518295:FANCM protein, human; D004265:DNA Helicases