Journal
GENES & DEVELOPMENT
Volume 25, Issue 17, Pages 1847-1858Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.17020911
Keywords
Fanconi anemia; deubiquitinating enzymes; PCNA; SUMO-like domains
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Funding
- International Human Frontier Science Program Organization
- Swiss Foundation for grants in biology and medicine
- Swiss National Science Foundation [PASMA3-119584]
- TOYOBO Biotechnology Foundation
- NIH [R01DK43889, R01HL52725, P01CA092584]
- Grants-in-Aid for Scientific Research [23221005] Funding Source: KAKEN
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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.
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