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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.

Pubmed ID: 21896657


  • Yang K
  • Moldovan GL
  • Vinciguerra P
  • Murai J
  • Takeda S
  • D'Andrea AD


Genes & development

Publication Data

September 1, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: P01 CA092584
  • Agency: NCI NIH HHS, Id: P01CA092584
  • Agency: NIDDK NIH HHS, Id: R01 DK043889
  • Agency: NIDDK NIH HHS, Id: R01DK43889
  • Agency: NHLBI NIH HHS, Id: R01HL52725

Mesh Terms

  • Adenosine Triphosphatases
  • Amino Acid Sequence
  • Animals
  • Arabidopsis Proteins
  • 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
  • Ubiquitin-Specific Proteases