Multiple ubiquitin ligases protect human genome integrity by targeting cancer-associated APOBEC3 deaminases for degradation
Multiple ubiquitin ligases protect human genome integrity by targeting cancer-associated APOBEC3 deaminases for degradation
Abstract Members of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family play crucial roles as antiviral restriction factors, yet some APOBEC3 (A3) members drive harmful hypermutation in humans, contributing to cancer. The cancer-associated A3 proteins are capable to transit from the cytosol to nucleus, driving genome mutations. Here, we show that the major cancer-associated members are efficiently removed by the ubiquitin-proteasome pathway, pointing to distinct cellular pathways protecting genomic DNA from hypermutation. Through genetic and proteomic screening UBR4, UBR5, and HUWE1 were identified as the ubiquitin E3 ligases marking cancer-associated A3B and A3H-I for degradation, thereby limiting A3-driven hypermutation. Mechanistically, UBR5 and HUWE1 recognize the unoccupied A3 RNA-binding domain, promoting proteasomal degradation. Depletion or mutation of the E3 ligases in cell models and cancer samples increased A3-driven genome mutagenesis. Our findings reveal UBR4, UBR5, and HUWE1 as crucial factors of a ubiquitination cascade maintaining human genome stability. HighlightsWhen not bound to RNA, APOBEC3 proteins enter the nucleus, driving genome mutations.UBR4, UBR5, and HUWE1 mark cancer-associated deaminases A3B and A3H-I for proteasomal degradation.The E3 ligases target the RNA-binding domain of A3s in their uncomplexed state.A distinct ubiquitination pathway protects genomic DNA from A3-mediated mutagenesis.
Menche J?rg、Scinicariello Sara、Schwartz Irene、Hornegger Harald、Hacker Kathrin、Schwartz Siegfried、Clausen Tim、Karag?z G. Elif、Versteeg Gijs A.、Hodakova Zuzana、Budroni Valentina、Meyenberg Mathilde、Haselbach David、Grabarczyk Daniel B.、Ehrmann Julian F.
Vienna BioCenter Campus (VBC)||University of Vienna, Center for Molecular Biology, Department of Structural and Computational Biology||CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences||Faculty of Mathematics, University of Vienna||Ludwig Boltzmann Institute for Network Medicine at the University of ViennaVienna BioCenter Campus (VBC)||University of Vienna, Center for Molecular Biology, Department of Microbiology||Vienna Biocenter PhD Program, a Doctoral School of the University of Vienna and the Medical University of ViennaVienna BioCenter Campus (VBC)||University of Vienna, Center for Molecular Biology, Department of Microbiology||Vienna Biocenter PhD Program, a Doctoral School of the University of Vienna and the Medical University of ViennaVienna BioCenter Campus (VBC)||Vienna Biocenter PhD Program, a Doctoral School of the University of Vienna and the Medical University of Vienna||Medical University of Vienna, Center for Medical Biochemistry, Department of Molecular BiologyVienna BioCenter Campus (VBC)||University of Vienna, Center for Molecular Biology, Department of MicrobiologyFaculty of InformaticsResearch Institute of Molecular Pathology (IMP), Vienna BioCenter Campus (VBC), Campus-Vienna-Biocenter 1||Medical University of Vienna, Vienna BioCenter (VBC)Vienna BioCenter Campus (VBC)||Medical University of Vienna, Center for Medical Biochemistry, Department of Molecular BiologyVienna BioCenter Campus (VBC)||University of Vienna, Center for Molecular Biology, Department of MicrobiologyResearch Institute of Molecular Pathology (IMP), Vienna BioCenter Campus (VBC), Campus-Vienna-Biocenter 1Vienna BioCenter Campus (VBC)||University of Vienna, Center for Molecular Biology, Department of Microbiology||Vienna Biocenter PhD Program, a Doctoral School of the University of Vienna and the Medical University of ViennaVienna BioCenter Campus (VBC)||University of Vienna, Center for Molecular Biology, Department of Structural and Computational Biology||CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesResearch Institute of Molecular Pathology (IMP), Vienna BioCenter Campus (VBC), Campus-Vienna-Biocenter 1||Medical University of Vienna, Vienna BioCenter (VBC)Research Institute of Molecular Pathology (IMP), Vienna BioCenter Campus (VBC), Campus-Vienna-Biocenter 1Vienna Biocenter PhD Program, a Doctoral School of the University of Vienna and the Medical University of Vienna||Research Institute of Molecular Pathology (IMP), Vienna BioCenter Campus (VBC), Campus-Vienna-Biocenter 1||Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School||Boston Children?ˉs Hospital
基础医学遗传学分子生物学
APOBECcytidine deaminaseE3 ligaseubiquitinproteasomeprotein degradationgenome integrityAPOBEC signatureRNA bindingDNA hypermutationUBR4UBR5HUWE1
Menche J?rg,Scinicariello Sara,Schwartz Irene,Hornegger Harald,Hacker Kathrin,Schwartz Siegfried,Clausen Tim,Karag?z G. Elif,Versteeg Gijs A.,Hodakova Zuzana,Budroni Valentina,Meyenberg Mathilde,Haselbach David,Grabarczyk Daniel B.,Ehrmann Julian F..Multiple ubiquitin ligases protect human genome integrity by targeting cancer-associated APOBEC3 deaminases for degradation[EB/OL].(2025-03-28)[2025-04-29].https://www.biorxiv.org/content/10.1101/2024.04.23.590688.点此复制
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