title: The MHF complex senses branched DNA by binding a pair of crossover DNA duplexes.
abstract: The conserved MHF1-MHF2 (MHF) complex functions in the activation of the Fanconi anaemia pathway of the DNA damage response, in regulating homologous recombination, and in DNA replication fork maintenance. MHF facilitates the processing of multiple types of branched DNAs by the DNA translocase FANCM. Here we report the crystal structure of a human MHF-DNA complex that reveals the DNA-binding mode of MHF. The structure suggests that MHF prefers branched DNA over double-stranded DNA because it engages two duplex arms. Biochemical analyses verify that MHF preferentially engages DNA forks or various four-way junctions independent of the junction-site structure. Furthermore, genetic experiments provide evidence that the observed DNA-binding interface of MHF is important for cellular resistance to DNA damage. These results offer insights into how the MHF complex recognizes branched DNA and stimulates FANCM activity at such a structure to promote genome maintenance.
authors.affiliation: 1] Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2].
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: 1] Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2].
authors.forename: Dorina
authors.initials: D
authors.lastname: Saro
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Sachpatzidis
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Thiyam Ramsing
authors.initials: TR
authors.lastname: Singh
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schlingman
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zheng
authors.affiliation: Department of Applied Physics, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mack
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
authors.forename: Miaw-Sheue
authors.initials: MS
authors.lastname: Tsai
authors.affiliation: 1] Department of Applied Physics, Yale University, New Haven, Connecticut 06511, USA [2] Department of Physics, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Mochrie
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Regan
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Amom Ruhikanta
authors.initials: AR
authors.lastname: Meetei
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sung
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / 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; D004247:DNA; C518295:FANCM protein, human; D004265:DNA Helicases