CRL4: Coupling Genome Stability to Ubiquitination.

The cullin-RING E3 ubiquitin ligase CRL4 has emerged as a master regulator of genome stability, which targets key cell cycle proteins for proteolysis during S phase and after DNA damage. Recent advances shed light on how it couples ubiquitination to DNA synthesis, offering a new paradigm for substrate recognition: Cdt2 binds directly onto proliferating cell nuclear antigen (PCNA) loaded on DNA, which serves as a landing pad for the independent recruitment of the ubiquitin ligase and its substrates. Cyclin-dependent kinases (CDKs) and the ataxia telangiectasia and Rad3-related (ATR) kinase ensure accurate spatiotemporal regulation of CRL4 under normal conditions and upon DNA damage. Deregulation of Cdt2 is evident in malignancies and was recently highlighted as a major target of oncogenic viruses, supporting the therapeutic targeting of the ligase as a promising anticancer strategy.