Daniel B. Grabarczyk

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.

Editor’s summary Protein homeostasis in eukaryotes is managed in part by serial attachment of the protein ubiquitin to target proteins. The resulting polyubiquitin chains target the protein to the proteasome for degradation. So-called E4 ligases extend a nascent ubiquitin chain to reinforce the degradation signal. Grabarczyk et al. determined the cryo–electron microscopy structures of the human E4 ligase UBR4 with two protein cofactors that govern specificity.

Keywords innate immunity E3 ubiquitin ligase helicase ZNFX1 nucleic acid sensor non-canonical ubiquitination Introduction Innate immunity targets microbial invaders via pathogen-associated molecular patterns (PAMPs).1 Viruses are typically recognized by the presence of nucleic acids (NAs) in incorrect cellular compartments.