CDT1 (chromatin licensing and DNA replication factor 1)
2009-11-01 Rekha Deka  , Ranjan Tamuli   AffiliationDepartment of Biotechnology, Indian Institute of Technology Guwahati, Guwahati-781 039, Assam, India
DNA/RNA

Description
DNA size 5.48 kb; mRNA size 2674 bp; 10 exons.
Proteins

Description
546 amino acids; 60433 Da.
CDT1 contains cyclin binding motif 68-70 (3), and region for geminin interaction 150-190 (41). Cyclin-binding motif is the target for phosphorylation by cyclin A-dependent kinases, which results in the binding of Cdt1 to the F-box protein Skp2 and subsequent degradation. Interaction with geminin, a small regulatory protein active during S, G2, and M phases of the cell cycle, protects CDT1 from ubiquitin mediated degradation. Six natural variants, A135V (VAR-029163), R172C (VAR-029164), R234C (VAR-054504), T262A (VAR-054505), E456A (VAR-029165), and A537V (VAR-024408) have been reported.
Isoforms : There are three different isoforms, aApr07 (complete), bApr07 (partial), and cApr07 (COOH complete); all three isoforms putatively encode good proteins.
Post translational modifications : Phosphorylation occurs at position Thr29, Ser31, Ser318, Ser372, and Ser394; however, phosphorylation does not affect binding to geminin.
CDT1 contains cyclin binding motif 68-70 (3), and region for geminin interaction 150-190 (41). Cyclin-binding motif is the target for phosphorylation by cyclin A-dependent kinases, which results in the binding of Cdt1 to the F-box protein Skp2 and subsequent degradation. Interaction with geminin, a small regulatory protein active during S, G2, and M phases of the cell cycle, protects CDT1 from ubiquitin mediated degradation. Six natural variants, A135V (VAR-029163), R172C (VAR-029164), R234C (VAR-054504), T262A (VAR-054505), E456A (VAR-029165), and A537V (VAR-024408) have been reported.
Isoforms : There are three different isoforms, aApr07 (complete), bApr07 (partial), and cApr07 (COOH complete); all three isoforms putatively encode good proteins.
Post translational modifications : Phosphorylation occurs at position Thr29, Ser31, Ser318, Ser372, and Ser394; however, phosphorylation does not affect binding to geminin.
Expression
Widely expressed, highly expressed in liver, thymus, and predominantly expressed in uterus and cervix of female reproductive system.
Localisation
Nucleus.
Function
The CDT1 protein is required for the formation of the pre-replicative complexes. CDT1 cooperates with CDC6 to promote loading of the mini-chromosome maintenance complex (MCM2-7) onto chromatin to form pre-replication complex necessary for the initiation of DNA replication. Moreover, CDT1 associates with the CDC7 kinase and recruits CDC45 to chromatin during S phase. Chromatin-bound CDT1 is first stabilized and subsequently displaced by CDC7 activity, which ensures timely execution of DNA replication. CDT1 is also a potential oncogene; overexpression of CDT1 promotes rereplication and generates a DNA damage senescence and response that activates the antitumor barriers of senescence and apoptosis.
Regulation : CDT1 is regulated either by cell cycle dependent proteolysis during S and G2 phase or by geminin. Proteolysis of CDT1 during S and G2 phases is dependent on the CDK2 -cyclin A mediated phosphorylation of CDT1 and subsequent proteolysis by SCF-Skp2 complex. CDT1 activity is also inhibited by the tight binding of geminin that blocks the ability of CDT1 to load MCM2-7 onto DNA.
Regulation : CDT1 is regulated either by cell cycle dependent proteolysis during S and G2 phase or by geminin. Proteolysis of CDT1 during S and G2 phases is dependent on the CDK2 -cyclin A mediated phosphorylation of CDT1 and subsequent proteolysis by SCF-Skp2 complex. CDT1 activity is also inhibited by the tight binding of geminin that blocks the ability of CDT1 to load MCM2-7 onto DNA.
Homology
The percent identity below represents identity of CDT1 over an aligned region in UniGene.
-Mus musculus : 82 % (percent identity)
-Bos taurus : 76.2 %
-Canis familiaris : 74.54 %
-Rattus norvegicus : 74.49 %
-Xenopus laevis : 62.5 %
-Danio rerio : 60 %.
-Mus musculus : 82 % (percent identity)
-Bos taurus : 76.2 %
-Canis familiaris : 74.54 %
-Rattus norvegicus : 74.49 %
-Xenopus laevis : 62.5 %
-Danio rerio : 60 %.
Mutations
Note
The RRL --->AAA mutation in the cyclin binding motif abolishes the binding of Cyclin A-dependent protein kinases with CDT1.
Implicated in
Entity name
Lung carcinoma
Note
In a subset of non-small-cell lung carcinomas (NSCLCs), CDT1 is significantly overexpressed that is positively correlated with CDC6 levels. Overexpression of CDT1-CDC6 in concert with p53-mutation is associated with higher tumor growth values and frequent aneuploidy compared with tumor bearing intact p53. These suggest a synergistic effect between CDT1-CDC6 overexpression and mutant-p53 over tumor growth and chromosomal instability in non-small-cell lung carcinomas.
Entity name
Colon cancer
Note
CDT1 is highly expressed in human neoplastics lesions of the colon; however, its cell cycle phase specific expression profile appears to be preserved during human carcinogenesis. Overexpression of CDT1 results in rereplication, a form of endogenous DNA damage.
Entity name
Chromosomal damage
Note
Overexpression of CDT1 induces chromosomal damage and activation of ATM-Chk2 without rereplication, resulting in chromosomal instability in normal human foreskin fibroblasts (HFF2) immortalized by telomerase. Deregulated CDT1 overexpression causes chronic chromosomal damage and instability that can eventually results in carcinogenesis. CDT1 is also highly expressed in cancer cells CaSki, HeLa, LNcap, MCF7, MDAMB231, and Saos. Overexpression of CDT1 may be at least partly due to increased transcription or increased gene copy number and CDT1 protein levels are much less affected by contact inhibition.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 19054765 | 2009 | Human CDT1 associates with CDC7 and recruits CDC45 to chromatin during S phase. | Ballabeni A et al |
| 16273206 | 2005 | Expression of the licensing factors, Cdt1 and Geminin, in human colon cancer. | Bravou V et al |
| 14672932 | 2004 | The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells. | Cook JG et al |
| 1865750 | 1991 | Low pH medium induces calcium dependent release of CGRP from sensory nerves of guinea-pig dural venous sinuses. | Fanciullacci M et al |
| 18617514 | 2008 | Cdt1 and Cdc6 are destabilized by rereplication-induced DNA damage. | Hall JR et al |
| 16407242 | 2006 | An evolutionarily conserved function of proliferating cell nuclear antigen for Cdt1 degradation by the Cul4-Ddb1 ubiquitin ligase in response to DNA damage. | Hu J et al |
| 15466399 | 2004 | Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1. | Karakaidos P et al |
| 18006835 | 2007 | Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior. | Liontos M et al |
| 14993212 | 2004 | Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. | Sugimoto N et al |
| 15855168 | 2005 | Degradation of Cdt1 during S phase is Skp2-independent and is required for efficient progression of mammalian cells through S phase. | Takeda DY et al |
| 16835273 | 2006 | Deregulation of Cdt1 induces chromosomal damage without rereplication and leads to chromosomal instability. | Tatsumi Y et al |
| 15291814 | 2004 | Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell lines. | Xouri G et al |
| 14712211 | 2004 | The destruction box of human Geminin is critical for proliferation and tumor growth in human colon cancer cells. | Yoshida K et al |
Other Information
Locus ID:
NCBI: 81620
MIM: 605525
HGNC: 24576
Ensembl: ENSG00000167513
Variants:
dbSNP: 81620
ClinVar: 81620
TCGA: ENSG00000167513
COSMIC: CDT1
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000167513 | ENST00000301019 | Q9H211 |
| ENSG00000167513 | ENST00000569140 | H3BSY1 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 35412947 | 2022 | Long non-coding RNA-PCGEM1 contributes to prostate cancer progression by sponging microRNA miR-129-5p to enhance chromatin licensing and DNA replication factor 1 expression. | 0 |
| 36443564 | 2022 | The proliferation of atypical hepatocytes and CDT1 expression in noncancerous tissue are associated with the postoperative recurrence of hepatocellular carcinoma. | 4 |
| 35412947 | 2022 | Long non-coding RNA-PCGEM1 contributes to prostate cancer progression by sponging microRNA miR-129-5p to enhance chromatin licensing and DNA replication factor 1 expression. | 0 |
| 36443564 | 2022 | The proliferation of atypical hepatocytes and CDT1 expression in noncancerous tissue are associated with the postoperative recurrence of hepatocellular carcinoma. | 4 |
| 33338304 | 2021 | Successful pregnancies in an adult with Meier-Gorlin syndrome harboring biallelic CDT1 variants. | 2 |
| 33536335 | 2021 | SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors. | 26 |
| 34348833 | 2021 | Elevated expression of CDT1 in childhood acute lymphoblastic leukemia promotes cell proliferation, invasion and migration through activation of EMT. | 1 |
| 33338304 | 2021 | Successful pregnancies in an adult with Meier-Gorlin syndrome harboring biallelic CDT1 variants. | 2 |
| 33536335 | 2021 | SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors. | 26 |
| 34348833 | 2021 | Elevated expression of CDT1 in childhood acute lymphoblastic leukemia promotes cell proliferation, invasion and migration through activation of EMT. | 1 |
| 30649446 | 2019 | A DNA-binding domain in the C-terminal region of Cdt2 enhances the DNA synthesis-coupled CRL4Cdt2 ubiquitin ligase activity for Cdt1. | 2 |
| 30649446 | 2019 | A DNA-binding domain in the C-terminal region of Cdt2 enhances the DNA synthesis-coupled CRL4Cdt2 ubiquitin ligase activity for Cdt1. | 2 |
| 29442275 | 2018 | Five Novel Oncogenic Signatures Could Be Utilized as AFP-Related Diagnostic Biomarkers for Hepatocellular Carcinoma Based on Next-Generation Sequencing. | 16 |
| 30154187 | 2018 | Cdt1 stabilizes kinetochore-microtubule attachments via an Aurora B kinase-dependent mechanism. | 14 |
| 30281379 | 2018 | Cdt1 variants reveal unanticipated aspects of interactions with cyclin/CDK and MCM important for normal genome replication. | 8 |
Citation
Rekha Deka ; Ranjan Tamuli
CDT1 (chromatin licensing and DNA replication factor 1)
Atlas Genet Cytogenet Oncol Haematol. 2009-11-01
Online version: http://atlasgeneticsoncology.org/gene/44175/cdt1
