title: Promotion of RAD51-Mediated Homologous DNA Pairing by the RAD51AP1-UAF1 Complex.
abstract: The UAF1-USP1 complex deubiquitinates FANCD2 during execution of the Fanconi anemia DNA damage response pathway. As such, UAF1 depletion results in persistent FANCD2 ubiquitination and DNA damage hypersensitivity. UAF1-deficient cells are also impaired for DNA repair by homologous recombination. Herein, we show that UAF1 binds DNA and forms a dimeric complex with RAD51AP1, an accessory factor of the RAD51 recombinase, and a trimeric complex with RAD51 through RAD51AP1. Two small ubiquitin-like modifier (SUMO)-like domains in UAF1 and a SUMO-interacting motif in RAD51AP1 mediate complex formation. Importantly, UAF1 enhances RAD51-mediated homologous DNA pairing in a manner that is dependent on complex formation with RAD51AP1 but independent of USP1. Mechanistically, RAD51AP1-UAF1 co-operates with RAD51 to assemble the synaptic complex, a critical nucleoprotein intermediate in homologous recombination, and cellular studies reveal the biological significance of the RAD51AP1-UAF1 protein complex. Our findings provide insights into an apparently USP1-independent role of UAF1 in genome maintenance.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Fengshan
authors.initials: F
authors.lastname: Liang
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Simonne
authors.initials: S
authors.lastname: Longerich
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Miller
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Buzovetsky
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Maranon
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wiese
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: gary.kupfer@yale.edu.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Kupfer
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: patrick.sung@yale.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sung
mesh_terms: D000595:Amino Acid Sequence; D023902:Chromosome Pairing; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D059765:Homologous Recombination; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D051135:Rad51 Recombinase / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D004247:DNA; D051135:Rad51 Recombinase