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DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response

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  • Fengshan Liang

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Adam S. Miller

    (Yale University School of Medicine)

  • Simonne Longerich

    (Yale University School of Medicine)

  • Caroline Tang

    (Yale University School of Medicine
    Yale University School of Medicine)

  • David Maranon

    (Colorado State University)

  • Elizabeth A. Williamson

    (University of Texas Health Science Center at San Antonio)

  • Robert Hromas

    (University of Texas Health Science Center at San Antonio)

  • Claudia Wiese

    (Colorado State University)

  • Gary M. Kupfer

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Patrick Sung

    (Yale University School of Medicine
    University of Texas Health Science Center at San Antonio)

Abstract

Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.

Suggested Citation

  • Fengshan Liang & Adam S. Miller & Simonne Longerich & Caroline Tang & David Maranon & Elizabeth A. Williamson & Robert Hromas & Claudia Wiese & Gary M. Kupfer & Patrick Sung, 2019. "DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10408-5
    DOI: 10.1038/s41467-019-10408-5
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