CDT1
Developmental stage
Present during G1 and early S phase of the cell cycle. Degraded during the late S, G2, and M phases.
Domain
The PIP-box K+4 motif mediates both the interaction with PCNA and the recruitment of the DCX(DTL) complex: while the PIP-box interacts with PCNA, the presence of the K+4 submotif, recruits the DCX(DTL) complex, leading to its ubiquitination.
Function
Required for both DNA replication and mitosis (PubMed:11125146, PubMed:14993212, PubMed:21856198, PubMed:22581055, PubMed:26842564). DNA replication licensing factor, required for pre-replication complex assembly. Cooperates with CDC6 and the origin recognition complex (ORC) during G1 phase of the cell cycle to promote the loading of the mini-chromosome maintenance (MCM) complex onto DNA to generate pre-replication complexes (pre-RC) (PubMed:14672932). Required also for mitosis by promoting stable kinetochore-microtubule attachments (PubMed:22581055). Potential oncogene (By similarity).
Involvement in disease
Meier-Gorlin syndrome 4
MGORS4
A syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Two independent E3 ubiquitin ligase complexes, SCF(SKP2) and the DCX(DTL) complex, mediated CDT1 degradation in S phase. Ubiquitinated by the DCX(DTL) complex, in response to DNA damage, leading to its degradation. Ubiquitination by the DCX(DTL) complex is necessary to ensure proper cell cycle regulation and is PCNA-dependent: interacts with PCNA via its PIP-box, while the presence of the containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to its degradation. Phosphorylation at Thr-29 by CDK2 targets CDT1 for ubiquitination by SCF(SKP2) E3 ubiquitin ligase and subsequent degradation (PubMed:14993212). The interaction with GMNN protects it against ubiquitination. Deubiquitinated by USP37 (PubMed:27296872).
Phosphorylation by cyclin A-dependent kinases at Thr-29 targets CDT1 for ubiquitynation by SCF(SKP2) E3 ubiquitin ligase and subsequent degradation (PubMed:14993212). Phosphorylated at Thr-29 by MAPK8/JNK1, which blocks replication licensing in response to stress (PubMed:21856198). Binding to GMNN is not affected by phosphorylation.
Sequence Similarities
Belongs to the Cdt1 family.
Cellular localization
- Nucleus
- Chromosome
- Centromere
- Kinetochore
- Transiently localizes to kinetochores during prometaphase and metaphase.
Alternative names
DNA replication factor Cdt1, Double parked homolog, DUP, CDT1