CDT2

CDT2, also known as DCAF2, is a protein that acts as the substrate receptor for the CRL4 (CUL4-DDB1) E3 ubiquitin ligase complex. It is encoded by the human CDT2 gene and is conserved among eukaryotes. CDT2 directs the ubiquitination and degradation of key cell cycle regulators, coordinating DNA replication licensing with DNA synthesis.

The CRL4CDT2 complex targets several substrates to prevent rereplication and ensure proper S-phase progression. Notable substrates include CDT1, a licensing factor whose timely degradation prevents re-licensing of origins; SET8 (KMT5A), a histone H4K20 methyltransferase whose removal aids chromatin regulation during replication; and p21, a CDK inhibitor whose degradation can promote replication under certain conditions. Substrate recognition generally requires PCNA on chromatin and a PIP box in the substrate, linking CDT2 activity to replication forks.

In cell cycle control and genome stability, CDT2 acts to couple DNA replication licensing to DNA synthesis. Loss or depletion of CDT2 leads to accumulation of CDT1 and SET8, rereplication, DNA damage, and cell cycle arrest, often compromising cell viability. The protein is essential for viability in many model systems and plays a central role in maintaining genome integrity during replication stress.

Clinical relevance in cancer biology has emerged because CDT2 expression is altered in various tumors and can influence genome stability and cellular response to replication stress. Because disruption of CDT2 function induces replication stress and selective loss of rapidly dividing cells, CDT2 is studied as a potential target for cancer therapies, though its broader essential role warrants careful consideration in therapeutic contexts.