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Cell Rep. 2016 Jun 7;15(10):2118-2126. doi: 10.1016/j.celrep.2016.05.007. Epub 2016 May 26.

Promotion of RAD51-Mediated Homologous DNA Pairing by the RAD51AP1-UAF1 Complex.

Author information

1
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
2
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.
3
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
4
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.
5
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: patrick.sung@yale.edu.

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.

PMID:
27239033
PMCID:
PMC5381662
DOI:
10.1016/j.celrep.2016.05.007
[Indexed for MEDLINE]
Free PMC Article

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