title: Regulation of the Fanconi anemia pathway by a SUMO-like delivery network.
abstract: 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.
authors: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
authors: Kailin
authors: K
authors: Yang
authors: George-Lucian
authors: GL
authors: Moldovan
authors: Patrizia
authors: P
authors: Vinciguerra
authors: Junko
authors: J
authors: Murai
authors: Shunichi
authors: S
authors: Takeda
authors: Alan D
authors: AD
authors: D'Andrea
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D029681:Arabidopsis Proteins; D002460:Cell Line; D002645:Chickens; D004268:DNA-Binding Proteins / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D025841:Small Ubiquitin-Related Modifier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020080:Tandem Repeat Sequences / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases; D029681:Arabidopsis Proteins; D004268:DNA-Binding Proteins; D010450:Endopeptidases; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D025841:Small Ubiquitin-Related Modifier Proteins; D025801:Ubiquitin; D064570:Ubiquitin-Specific Proteases; C546328:ATAD5 protein, human; C526165:WDR48 protein, human; C579228:USP1 protein, human