Regulation of the Fanconi anemia pathway by a SUMO-like delivery network.

The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly ...
to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.
Mesh Terms:
Adenosine Triphosphatases, Amino Acid Sequence, Animals, Cell Line, Chickens, DNA-Binding Proteins, Endopeptidases, Fanconi Anemia Complementation Group Proteins, Gene Expression Regulation, Gene Knockdown Techniques, Hela Cells, Humans, Models, Molecular, Nuclear Proteins, Proliferating Cell Nuclear Antigen, Protein Binding, Protein Structure, Tertiary, Recombination, Genetic, Small Ubiquitin-Related Modifier Proteins, Tandem Repeat Sequences, Ubiquitin
Genes Dev.
Date: Sep. 01, 2011
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