2. Academic Validation
  3. Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein

Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein

  • PLoS Genet. 2018 Oct 18;14(10):e1007643. doi: 10.1371/journal.pgen.1007643.
Anna Motnenko 1,  Chih-Chao Liang 1,  Di Yang 1,  David Lopez-Martinez 1,  Yasunaga Yoshikawa 1,  Bao Zhan 1,  Katherine E Ward 1,  Jiayang Tian 1,  Wilhelm Haas 2,  Paolo Spingardi 3,  Benedikt M Kessler 4,  Skirmantas Kriaucionis 3,  Steven P Gygi 2,  Martin A Cohn 1
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
  • 2 Department of Cell Biology, Harvard Medical School, Boston, MA, United States of America Medicine, Kitasato University, Aomori, Japan.
  • 3 Ludwig Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
  • 4 Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
PMID: 30335751 DOI: 10.1371/journal.pgen.1007643
Abstract

The Fanconi Anemia (FA) pathway is important for repairing interstrand crosslinks (ICLs) between the Watson-Crick strands of the DNA double helix. An initial and essential stage in the repair process is the detection of the ICL. Here, we report the identification of UHRF2, a paralogue of UHRF1, as an ICL sensor protein. UHRF2 is recruited to ICLs in the genome within seconds of their appearance. We show that UHRF2 cooperates with UHRF1, to ensure recruitment of FANCD2 to ICLs. A direct protein-protein interaction is formed between UHRF1 and UHRF2, and between either UHRF1 and UHRF2, and FANCD2. Importantly, we demonstrate that the essential monoubiquitination of FANCD2 is stimulated by UHRF1/UHRF2. The stimulation is mediating by a retention of FANCD2 on chromatin, allowing for its monoubiquitination by the FA core complex. Taken together, we uncover a mechanism of ICL sensing by UHRF2, leading to FANCD2 recruitment and retention at ICLs, in turn facilitating activation of FANCD2 by monoubiquitination.

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