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

## TL;DR

This study shows how specific E3 ligases degrade harmful APOBEC3 proteins to prevent DNA mutations and maintain genome stability in humans.

## Contribution

The discovery of UBR4, UBR5, and HUWE1 as key E3 ligases targeting cancer-associated APOBEC3 proteins for degradation.

## Key findings

- UBR4, UBR5, and HUWE1 mark A3B and A3H-I for proteasomal degradation.
- E3 ligase depletion or mutation increases A3-driven genome mutagenesis in cells and cancer samples.
- These ligases recognize A3s without RNA binding, preventing harmful nuclear activity.

## 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.

APOBEC deaminases restrict retroviruses but can also mutate human DNA. Here, the authors show that cancerassociated APOBEC3s with low RNA binding, known to enter the nucleus, are selectively recognized by E3 ligases and degraded, eliminating harmful nuclear enzymes, and limiting genome mutation.