Journal article
Regulation of the Fanconi anemia pathway by a SUMO-like delivery network
Genes & development, Vol.25(17), pp.1847-1858
09/01/2011
DOI: 10.1101/gad.17020911
PMCID: PMC3175720
PMID: 21896657
Abstract
Protein deubiquitination is a critical regulatory mechanism employed in the multistep response to DNA damage. The deubiquitinating complex USP1/UAF1 coordinately regulates the homologous recombination pathway (via FANCD2/FANC1) and the translesion synthesis pathway (via hELG1 and PCNA). USP1/UAF1 is targeted to its substrates by a SUMO-like domain on UAF1, which binds to SIM motifs present on both FANC1 and the PCNA-binding protein hELG1.
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.
Details
- Title: Subtitle
- Regulation of the Fanconi anemia pathway by a SUMO-like delivery network
- Creators
- Kailin Yang - Harvard UniversityGeorge-Lucian MoldovanPatrizia Vinciguerra - Dana-Farber Cancer InstituteJunko Murai - Kyoto UniversityShunichi Takeda - Kyoto UniversityAlan D. D'Andrea
- Resource Type
- Journal article
- Publication Details
- Genes & development, Vol.25(17), pp.1847-1858
- Publisher
- Cold Spring Harbor Laboratory Press
- DOI
- 10.1101/gad.17020911
- PMID
- 21896657
- PMCID
- PMC3175720
- ISSN
- 0890-9369
- eISSN
- 1549-5477
- Alternative title
- Yang et al
- Language
- English
- Date published
- 09/01/2011
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696585202771
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