CRL4Cdt2

CRL4Cdt2 is a Cullin-RING ubiquitin ligase complex that forms part of the CRL4 family. It consists of the cullin scaffold Cul4A or Cul4B, the adaptor protein DDB1, and the substrate receptor Cdt2, which acts as a DCAF (DDB1-CUL4 associated factor). The complex targets substrates for ubiquitination when they are bound to PCNA on chromatin, using a PIP degron in the substrate to recruit to the ligase.

Known substrates include Cdt1, p21, and Set8/PR-Set7; these proteins are degraded to prevent re-replication and to regulate DNA replication and chromatin state during S phase and after DNA damage. By promoting timely degradation of these factors, CRL4Cdt2 helps control replication licensing and the cell cycle in response to replication stress or DNA lesions.

CRL4Cdt2 plays a key role in licensing control, the DNA damage response, and genome stability, contributing to proper progression through S phase and maintaining chromatin integrity. Its activity is closely tied to PCNA interactions on chromatin, which recruit PCNA-bound substrates bearing a degron to the ligase for ubiquitination and subsequent degradation by the proteasome.

The complex is evolutionarily conserved from yeast to humans. In humans, the core components are Cul4A/B, DDB1, and CDT2. Dysregulation of CRL4Cdt2 or its substrates can lead to genome instability and has been discussed in the context of cancer biology, highlighting its importance in maintaining genomic integrity.