Multiple ubiquitin ligases protect human genome integrity by targeting cancer-associated APOBEC3 deaminases for degradation
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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.
Highlights
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When not bound to RNA, APOBEC3 proteins enter the nucleus, driving genome mutations.
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UBR4, UBR5, and HUWE1 mark cancer-associated deaminases A3B and A3H-I for proteasomal degradation.
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The E3 ligases target the RNA-binding domain of A3s in their uncomplexed state.
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A distinct ubiquitination pathway protects genomic DNA from A3-mediated mutagenesis.