title: The structure of the FANCM-MHF complex reveals physical features for functional assembly.
abstract: Fanconi anaemia is a rare genetic disease characterized by chromosomal instability and cancer susceptibility. The Fanconi anaemia complementation group protein M (FANCM) forms an evolutionarily conserved DNA-processing complex with MHF1/MHF2 (histone-fold-containing proteins), which is essential for DNA repair in response to genotoxic stress. Here we present the crystal structures of the MHF1-MHF2 complex alone and bound to a fragment of FANCM (FANCM(661-800), designated FANCM-F). The structures show that MHF1 and MHF2 form a compact tetramer to which FANCM-F binds through a 'dual-V' shaped structure. FANCM-F and (MHF1-MHF2)(2) cooperate to constitute a new DNA-binding site that is coupled to the canonical L1L2 region. Perturbation of the MHF-FANCM-F structural plasticity changes the localization of FANCM in vivo. The MHF-FANCM interaction and its subcellular localization are altered by a disease-associated mutant of FANCM. These findings reveal the molecular basis of MHF-FANCM recognition and provide mechanistic insights into the pathway leading to Fanconi anaemia.
authors.affiliation: Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, China.
authors.forename: Yuyong
authors.initials: Y
authors.lastname: Tao
authors.forename: Changjiang
authors.initials: C
authors.lastname: Jin
authors.forename: Xu
authors.initials: X
authors.lastname: Li
authors.forename: Shali
authors.initials: S
authors.lastname: Qi
authors.forename: Lingluo
authors.initials: L
authors.lastname: Chu
authors.forename: Liwen
authors.initials: L
authors.lastname: Niu
authors.forename: Xuebiao
authors.initials: X
authors.lastname: Yao
authors.forename: Maikun
authors.initials: M
authors.lastname: Teng
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004265:DNA Helicases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005199:Fanconi Anemia / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C493243:CENPS protein, human; C551977:CENPX protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C518295:FANCM protein, human; D004265:DNA Helicases