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Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity.

Author information

Affiliations

  • 1. Max Perutz Labs, Vienna BioCenter Campus (VBC), Dr. -Bohrgasse 9, Vienna, Austria.
      Authors
    • Schwartz I 1, 4
    • Budroni V 1, 4
    • Meyenberg M 1
    • Hornegger H 1, 4
    • Hacker K 1
    • Scinicariello S 1, 4
    • Menche J 1
    • Karagöz GE 1
    • Versteeg GA 1
    (9 authors)
  • 2. Research Institute of Molecular Pathology (IMP), Vienna BioCenter Campus (VBC), Vienna, Austria.
      Authors
    • Hodakova Z 2
    • Grabarczyk DB 2
    • Ehrmann JF 2, 4
    • Haselbach D 2
    • Clausen T 2
    (5 authors)
  • 3. TU Wien, Faculty of Informatics, Vienna, Austria.
      Authors
    • Schwartz S 3
    (1 author)
  • 4. Vienna Biocenter PhD Program, a Doctoral School of the University of Vienna and the Medical University of Vienna, Vienna, Austria.
      Authors
    • Schwartz I 1, 4
    • Budroni V 1, 4
    • Hornegger H 1, 4
    • Ehrmann JF 2, 4
    • Scinicariello S 1, 4
    (5 authors)

ORCIDs linked to this article

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Nature Communications, 19 Jan 2026,
https://doi.org/10.1038/s41467-026-68420-5 PMID: 41554709 

This article is based on a previously available preprint.

Abstract 

APOBEC family members play crucial roles in antiviral restriction. However, certain APOBEC3 (A3) proteins drive harmful hypermutation in humans, contributing to cancer. The cancer-associated A3 proteins are capable of transiting from the cytosol to the nucleus, where they can cause genome mutations. Here, we uncover a specific set of cellular pathways that protect genomic DNA from the major cancer-associated A3 proteins. Through genetic and proteomic screening, we identify UBR4, UBR5, and HUWE1 as key ubiquitin E3 ligases marking cancer-associated A3B and A3H-I for degradation, thereby limiting A3-driven hypermutation. Mechanistically, UBR5 and HUWE1 recognize A3s in the absence of their RNA binding partner, thus promoting proteasomal degradation of APOBEC3 protein that is not engaged in its antiviral cellular function. Depletion or mutation of the E3 ligases in cells and human cancer samples increases A3-driven genome mutagenesis. Our findings reveal that UBR4, UBR5, and HUWE1 are crucial factors in a ubiquitination cascade that maintains human genome stability.

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Read article at publisher's site: https://doi.org/10.1038/s41467-026-68420-5

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    Funding 

    Funders who supported this work.

    Austrian Science Fund FWF (3)

    • Grant ID: 10.55776/W1261

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    • Grant ID: 10.55776/F79

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    • Grant ID: 10.55776/P36945

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