title: Structural insights into the functions of the FANCM-FAAP24 complex in DNA repair.
abstract: Fanconi anemia (FA) is a genetically heterogeneous disorder associated with deficiencies in the FA complementation group network. FA complementation group M (FANCM) and FA-associated protein 24 kDa (FAAP24) form a stable complex to anchor the FA core complex to chromatin in repairing DNA interstrand crosslinks. Here, we report the first crystal structure of the C-terminal segment of FANCM in complex with FAAP24. The C-terminal segment of FANCM and FAAP24 both consist of a nuclease domain at the N-terminus and a tandem helix-hairpin-helix (HhH)2 domain at the C-terminus. The FANCM-FAAP24 complex exhibits a similar architecture as that of ApXPF. However, the variations of several key residues and the electrostatic property at the active-site region render a catalytically inactive nuclease domain of FANCM, accounting for the lack of nuclease activity. We also show that the first HhH motif of FAAP24 is a potential binding site for DNA, which plays a critical role in targeting FANCM-FAAP24 to chromatin. These results reveal the mechanistic insights into the functions of FANCM-FAAP24 in DNA repair.
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China, Graduate School of Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China and Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Tianlong
authors.initials: T
authors.lastname: Zhang
authors.forename: Ye
authors.initials: Y
authors.lastname: Tao
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
authors.forename: Jianping
authors.initials: J
authors.lastname: Ding
mesh_terms: D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases / Q000737:chemistry* / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D054730:Protein Interaction Domains and Motifs
chemical_list: D004268:DNA-Binding Proteins; C518296:FAAP24 protein, human; D051856:Fanconi Anemia Complementation Group Proteins; D004247:DNA; C518295:FANCM protein, human; D004265:DNA Helicases