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

Kailin Yang, George Lucian Moldovan, Patrizia Vinciguerra, Junko Murai, Shunichi Takeda, Alan D. D'Andrea

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1847-1858
Number of pages12
JournalGenes and Development
Volume25
Issue number17
DOIs
StatePublished - Sep 1 2011

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

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