Deltex E3s modify ADP-ribosylated targets with ubiquitin, creating a hybrid modification whose readers remains unknown. Here, the authors synthesise a non-hydrolysable probe that mimics the modificati...

Host AAA-ATPase VCP/p97 binds and extracts ubiquitinated proteins from the bacterial cell membrane causing bacterial lysis and death to confer cell-autonomous protection against infection.

During starvation, TFEB activates SQSTM1-dependent autophagy to degrade ubiquitinated ribosomal components.

An antibody-based approach to enrich ubiquitinated peptides reveals Arabidopsis root, seedling, and leaf ubiquitinomes.

Host AAA-ATPase VCP/p97 binds and extracts ubiquitinated proteins from the bacterial cell membrane causing bacterial lysis and death to confer cell-autonomous protection against infection.

The proliferating cell nuclear antigen (PCNA) sliding clamp is a central component of eukaryotic DNA synthesis. In response to DNA damage, PCNA is mono-ubiquitinated by the RAD6 (E2)-RAD18 (E3) complex. However, the structural basis by which RAD18 engages PCNA to direct mono-ubiquitination has remained poorly defined. Mono-ubiquitinated PCNA can subsequently be extended with K48-linked poly-ubiquitin chains that target PCNA for degradation. Ubiquitin-specific protease 1 (USP1) reverses both mono- and poly-ubiquitination of PCNA; accordingly, USP1 inhibition promotes accumulation of mono-ubiquitinated PCNA at replication forks and reduces total PCNA levels, leading to replication defects that are synthetically lethal with BRCA1 deficiency. Here, we combine computational and structural approaches to identify and characterize a SAP domain PCNA-interacting peptide (PIP) motif within RAD18. We demonstrate that this interaction is required for DNA damage-induced PCNA mono-ubiquitination and for PCNA turnover following USP1 loss. Disruption of the RAD18-PCNA interface suppresses ssDNA gap accumulation and reduces USP1 inhibitor sensitivity in BRCA1-deficient cells. Furthermore, cells adapted to prolonged USP1 inhibition exhibit reduced RAD18 levels, suggesting that deregulation of PCNA mono-ubiquitination represents a biologically relevant resistance mechanism. Together, these findings define a structural interface required for RAD18-dependent PCNA mono-ubiquitination and establish it as a key determinant of USP1-BRCA1 synthetic lethality. ### Competing Interest Statement A.D.D. reports consulting for Bayer AG, Bristol Myers Squibb, EMD Serono, Impact Therapeutics, Tango Therapeutics, Roche Pharma, and Covant, Therapeutics; is an Advisory Board member for Impact Therapeutics; and reports receiving commercial research grants from EMD Serono, Moderna, and Tango Therapeutics The Ludwig Center at Harvard National Institutes of Health, https://ror.org/01cwqze88, R35GM156397

Nature Reviews Molecular Cell Biology, Published online: 31 October 2025; doi:10.1038/s41580-025-00919-zIn this Tools of the Trade article, Kiss (Schulman lab) discusses the development of UbiREAD, a method that delivers in vitro-ubiquitinated protein reporters into cells to systematically assess how different ubiquitin chain configurations affect protein stability and degradation.

The AAA-ATPase, p97, binds ubiquitinated bacterial surface proteins, extracting them with a mechanical force that disrupts and lyses the bacterial cell envelope. Thus, ubiquitination and proteasomal t...

Li et al. discovered that the cytotoxic synthetic small molecule BRD1732 is directly ubiquitinated in cells. Ubiquitination of BRD1732 is E3 ligase dependent and leads to inhibition of proteasomal deg...

p62/SQSTM1 self-assembles with polyubiquitin into liquid-like condensates (“p62 bodies”) that function as stress-signaling hubs and selective autophagy cargo. We show that TBK1-dependent phosphorylati...

Ubiquitin chains determine the fates of their modified proteins, including proteasomal degradation. Kiss et al. present UbiREAD, a technology to monitor cellular degradation and deubiquitination at high temporal resolution after intracellular delivery of ubiquitinated proteins. This reveals a degradation code for ubiquitin chains varying by linkage, length, and topology.

Deltex E3s modify ADP-ribosylated targets with ubiquitin, creating a hybrid modification whose readers remains unknown. Here, the authors synthesise a non-hydrolysable probe that mimics the modificati...

In absence of oxidative stress (i.e., Control, left panel) Keap1 binds and ubiquitinates the antioxidant response element (ARE) transcription factor NRF2. Ubiquitinated NRF2 is degraded and unable to....