Guard the guardian: A CRL4 ligase stands watch over histone production

Histones are evolutionarily conserved proteins that together with DNA constitute eukaryotic chromatin in a defined stoichiometry. Core histones are dynamic scaffolding proteins that undergo a myriad of post-translational modifications, which selectively engage chromosome condensation, replication, transcription and DNA damage repair. Cullin4-RING ubiquitin E3 ligases are known to hold pivotal roles in a wide spectrum of chromatin biology ranging from chromatin remodeling and transcriptional repression, to sensing of cytotoxic DNA lesions. Our recent work uncovers an unexpected function of a CRL4 ligase upstream of these processes in promoting histone biogenesis. The CRL4^WDR23 ligase directly controls the activity of the stem-loop binding protein (SLBP), which orchestrates elemental steps of canonical histone transcript metabolism. We demonstrate that non-proteolytic ubiquitination of SLBP ensures sufficient histone reservoirs during DNA replication and is vital for genome integrity and cellular fitness.