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

  • Nat Commun. 2026 Jan 19;17(1):1723. doi: 10.1038/s41467-026-68420-5.
Irene Schwartz  #  1  2  3 ,  Valentina Budroni  #  1  2  3 ,  Mathilde Meyenberg  1  4  5 ,  Zuzana Hodakova  6 ,  Harald Hornegger  1  3  7 ,  Kathrin Hacker  1  2 ,  Siegfried Schwartz  8 ,  Daniel B Grabarczyk  6 ,  Julian F Ehrmann  3  6  9  10 ,  Sara Scinicariello  1  2  3 ,  David Haselbach  6  11 ,  Jörg Menche  1  2  4  5  12 ,  Tim Clausen  6  11 ,  G Elif Karagöz  1  7 ,  Gijs A Versteeg  13  14
Affiliations
  • 1. Max Perutz Labs, Vienna BioCenter Campus (VBC), Dr. -Bohrgasse 9, Vienna, Austria.
  • 2. University of Vienna, Center for Molecular Biology, Dr. -Bohrgasse 9, Vienna, Austria.
  • 3. Vienna Biocenter PhD Program, a Doctoral School of the University of Vienna and the Medical University of Vienna, Vienna, Austria.
  • 4. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 5. Ludwig Boltzmann Institute for Network Medicine at the University of Vienna, Vienna, Austria.
  • 6. Research Institute of Molecular Pathology (IMP), Vienna BioCenter Campus (VBC), Vienna, Austria.
  • 7. Medical University of Vienna, Center for Medical Biochemistry, Dr. -Bohrgasse 9, Vienna, Austria.
  • 8. TU Wien, Faculty of Informatics, Vienna, Austria.
  • 9. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 10. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
  • 11. Medical University of Vienna, Vienna BioCenter (VBC), Vienna, Austria.
  • 12. Faculty of Mathematics, University of Vienna, Vienna, Austria.
  • 13. Max Perutz Labs, Vienna BioCenter Campus (VBC), Dr. -Bohrgasse 9, Vienna, Austria. [email protected].
  • 14. University of Vienna, Center for Molecular Biology, Dr. -Bohrgasse 9, Vienna, Austria. [email protected].
  • # Contributed equally.
PMID: 41554709 DOI: 10.1038/s41467-026-68420-5
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.