title: Molecular basis for enhancement of the meiotic DMC1 recombinase by RAD51 associated protein 1 (RAD51AP1).
abstract: Homologous recombination is needed for meiotic chromosome segregation, genome maintenance, and tumor suppression. RAD51AP1 (RAD51 associated protein 1) has been shown to interact with and enhance the recombinase activity of RAD51. Accordingly, genetic ablation of RAD51AP1 leads to enhanced sensitivity to and also chromosome aberrations upon DNA damage, demonstrating a role for RAD51AP1 in mitotic homologous recombination. Here we show physical association of RAD51AP1 with the meiosis-specific recombinase DMC1 and a stimulatory effect of RAD51AP1 on the DMC1-mediated D-loop reaction. Mechanistic studies have revealed that RAD51AP1 enhances the ability of the DMC1 presynaptic filament to capture the duplex-DNA partner and to assemble the synaptic complex, in which the recombining DNA strands are homologously aligned. We also provide evidence that functional cooperation is dependent on complex formation between DMC1 and RAD51AP1 and that distinct epitopes in RAD51AP1 mediate interactions with RAD51 and DMC1. Finally, we show that RAD51AP1 is expressed in mouse testes, and that RAD51AP1 foci colocalize with a subset of DMC1 foci in spermatocytes. These results suggest that RAD51AP1 also serves an important role in meiotic homologous recombination.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA. eloise.dray@yale.edu
authors.forename: Eloïse
authors.initials: E
authors.lastname: Dray
authors.forename: Myun Hwa
authors.initials: MH
authors.lastname: Dunlop
authors.forename: Liisa
authors.initials: L
authors.lastname: Kauppi
authors.forename: Joseph
authors.initials: J
authors.lastname: San Filippo
authors.forename: Claudia
authors.initials: C
authors.lastname: Wiese
authors.forename: Miaw-Sheue
authors.initials: MS
authors.lastname: Tsai
authors.forename: Sead
authors.initials: S
authors.lastname: Begovic
authors.forename: David
authors.initials: D
authors.lastname: Schild
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.forename: Scott
authors.initials: S
authors.lastname: Keeney
authors.forename: Patrick
authors.initials: P
authors.lastname: Sung
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D023902:Chromosome Pairing; D004268:DNA-Binding Proteins / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D008297:Male; D008540:Meiosis; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D011485:Protein Binding; D020033:Protein Isoforms / Q000302:isolation & purification / Q000378:metabolism; D021381:Protein Transport; D016601:RNA-Binding Proteins; D051135:Rad51 Recombinase / Q000378:metabolism; D045522:Recombinases / Q000378:metabolism*; D013090:Spermatocytes / Q000166:cytology / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C513032:Dmc1 protein, mouse; D050505:Mutant Proteins; D009687:Nuclear Proteins; D009841:Oligonucleotides; D028044:Phosphate-Binding Proteins; D020033:Protein Isoforms; C110410:RAD51AP1 protein, human; D016601:RNA-Binding Proteins; C106710:Rad51ap1 protein, mouse; D045522:Recombinases; D051135:Rad51 Recombinase; C074556:DMC1 protein, human