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Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48

Author

Listed:
  • Georgia Velimezi

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Lydia Robinson-Garcia

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Francisco Muñoz-Martínez

    (University of Cambridge)

  • Wouter W. Wiegant

    (Leiden University Medical Center, Leiden)

  • Joana Ferreira da Silva

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Michel Owusu

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Martin Moder

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Marc Wiedner

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Sara Brin Rosenthal

    (University of California, San Diego)

  • Kathleen M. Fisch

    (University of California, San Diego)

  • Jason Moffat

    (University of Toronto)

  • Jörg Menche

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Haico van Attikum

    (Leiden University Medical Center, Leiden)

  • Stephen P. Jackson

    (University of Cambridge)

  • Joanna I. Loizou

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

Abstract

Defects in DNA repair can cause various genetic diseases with severe pathological phenotypes. Fanconi anemia (FA) is a rare disease characterized by bone marrow failure, developmental abnormalities, and increased cancer risk that is caused by defective repair of DNA interstrand crosslinks (ICLs). Here, we identify the deubiquitylating enzyme USP48 as synthetic viable for FA-gene deficiencies by performing genome-wide loss-of-function screens across a panel of human haploid isogenic FA-defective cells (FANCA, FANCC, FANCG, FANCI, FANCD2). Thus, as compared to FA-defective cells alone, FA-deficient cells additionally lacking USP48 are less sensitive to genotoxic stress induced by ICL agents and display enhanced, BRCA1-dependent, clearance of DNA damage. Consequently, USP48 inactivation reduces chromosomal instability of FA-defective cells. Our results highlight a role for USP48 in controlling DNA repair and suggest it as a potential target that could be therapeutically exploited for FA.

Suggested Citation

  • Georgia Velimezi & Lydia Robinson-Garcia & Francisco Muñoz-Martínez & Wouter W. Wiegant & Joana Ferreira da Silva & Michel Owusu & Martin Moder & Marc Wiedner & Sara Brin Rosenthal & Kathleen M. Fisch, 2018. "Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04649-z
    DOI: 10.1038/s41467-018-04649-z
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    Cited by:

    1. Pisanu Buphamalai & Tomislav Kokotovic & Vanja Nagy & Jörg Menche, 2021. "Network analysis reveals rare disease signatures across multiple levels of biological organization," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Bert Kooij & Fenna J. Wal & Magdalena B. Rother & Wouter W. Wiegant & Pau Creixell & Merula Stout & Brian A. Joughin & Julia Vornberger & Matthias Altmeyer & Marcel A. T. M. Vugt & Michael B. Yaffe & , 2024. "The Fanconi anemia core complex promotes CtIP-dependent end resection to drive homologous recombination at DNA double-strand breaks," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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