title: Significance of ligand interactions involving Hop2-Mnd1 and the RAD51 and DMC1 recombinases in homologous DNA repair and XX ovarian dysgenesis.
abstract: The evolutionarily conserved Hop2-Mnd1 complex is a key cofactor for the meiosis-specific recombinase Dmc1. However, emerging evidence has revealed that Hop2-Mnd1 is expressed in somatic tissues, primary human fibroblasts and cell lines, and that it functions in conjunction with the Rad51 recombinase to repair damaged telomeres via the alternate lengthening of telomeres mechanism. Here, we reveal how distinct DNA-binding activities of Hop2-Mnd1 mediate the stabilization of the RAD51-ssDNA presynaptic filament or stimulate the homologous DNA pairing reaction. We have also endeavored to define the interface that governs the assembly of the higher order complex of Hop2-Mnd1 with RAD51. Unexpectedly, we find that ATP enhances the interaction between Hop2-Mnd1 and RAD51, and that both Hop2 and Mnd1 are involved in RAD51 interaction via their C-terminal regions. Importantly, mutations introduced into these Hop2 and Mnd1 domains, including the HOP2 p.del201Glu mutation present in a patient of XX ovarian dysgenesis, diminish the association and functional synergy of Hop2-Mnd1 with both RAD51 and DMC1. Our findings help delineate the intricate manner in which Hop2-Mnd1 engages and functions with RAD51 and DMC1 in mammalian cells and speak to the possible cause of XX ovarian dysgenesis.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA patrick.sung@yale.edu.
authors.forename: Weixing
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA weixing.zhao@yale.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sung
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D023961:Gonadal Dysgenesis, 46,XX / Q000235:genetics*; D006801:Humans; D008024:Ligands; D051379:Mice; D017354:Point Mutation; D054730:Protein Interaction Domains and Motifs; D051135:Rad51 Recombinase / Q000737:chemistry / Q000378:metabolism*; D059767:Recombinational DNA Repair
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C501202:Hop2 protein, mouse; D008024:Ligands; C501203:Mnd1 protein, mouse; D000255:Adenosine Triphosphate; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C074556:DMC1 protein, human
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