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.