Regulation of the Fanconi anemia pathway by a SUMO-like delivery network (original) (raw)

  1. George-Lucian Moldovan1,
  2. Patrizia Vinciguerra1,
  3. Junko Murai3,
  4. Shunichi Takeda3 and
  5. Alan D. D'Andrea1,4
  6. 1Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
  7. 2Leder Human Biology Program, Biological and Biomedical Sciences Program, Harvard Medical School, Boston, Massachusetts 02115, USA;
  8. 3Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan

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.

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