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CDC7 (cell division cycle 7)

Written2020-02Hugo Passos Vicari, João Agostinho Machado-Neto
Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, Brazil; hugopassosvicari@hotmail.com; jamachadoneto@usp.br

Abstract CDC7 is a serine-threonine kinase that participates in multiple cellular processes, including DNA replication, chromosomal segregation, S phase cell cycle progression, and DNA damage checkpoint. CDC7 is frequently highly expressed in several types of neoplasm, and it has been associated with cancer development and poor clinical outcomes. In different cancer models, functional studies indicated that CDC7 may be an attractive target for antineoplastic therapy, and CDC7 inhibitors have been developed. The present review on CDC7 contains data on DNA/RNA, the protein encoded, and the implication of this gene in cancer cell biology and clinical outcomes.

Keywords CDC7; DDK; DNA replication; Chromosome segregation; DNA damage checkpoint

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Identity

Alias (NCBI)Hsk1
CDC7L1
HsCDC7
huCDC7
HGNC (Hugo) CDC7
HGNC Alias symbHsk1
huCdc7
HsCdc7
HGNC Previous nameCDC7L1
HGNC Previous nameCDC7 (cell division cycle 7, S. cerevisiae, homolog)-like 1
 CDC7 cell division cycle 7 (S. cerevisiae)
 cell division cycle 7 (S. cerevisiae)
 cell division cycle 7 homolog (S. cerevisiae)
LocusID (NCBI) 8317
Atlas_Id 40015
Location 1p22.1  [Link to chromosome band 1p22]
Location_base_pair Starts at 91500851 and ends at 91525764 bp from pter ( according to hg19-Feb_2009)  [Mapping CDC7.png]
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Description The entire CDC7 gene is approximately 24.9 Kb (start: 91500851 and end: 91525764 bp; orientation: Plus strand). On the NCBI database (https://www.ncbi.nlm.nih.gov/gene), there are 3 transcript variants (exons: 12, coding exons: 11) for CDC7 that encode for the same protein (574 amino acids [aa]): the transcript variant 1 represents the most commonly occurring transcript (transcript length: 3215 bp); the transcript variant 2 presents a different splice site in the 5' UTR (transcript length: 3188 bp), while the transcript variant 3 has different segment for part of its 5' UTR (transcript length: 3316 bp). On the Ensembl database (http://www.ensembl.org/), there are 3 additional transcript variants for CDC7: one transcript variant has 6 exons (5 coding exons), length of 701 bp, and encode a 157 aa protein, and two transcript variant that encodes no protein (one with 4 exons and length of 729 bp, and other with 4 exons and length of 594 bp).

Protein

 
  Figure 1. Schematic structure of CDC7 protein. (A) The CDC7 protein presents 574 aa and contains a protein kinase domain that is responsible for its activity. The position of amino acids is indicated in the Figure. The 3D reconstitution of CDC7 protein was constructed using Swiss-model platform (https://swissmodel.expasy.org/), and cartoon (B) and surface (C) versions of the protein are illustrated.
Description CDC7 protein consists of 574 aminoacids (aa) with a molecular weight of 64 kDa and has a conserved protein kinase domain (58-574 aa) in the C-terminal region. The schematic representation of the CDC7 protein is illustrated in Figure 1.
Expression Ubiquitous.
Localisation Nucleoplasm, cytokinetic bridge, and mitotic spindle.
 
  Figure 2. CDC7-mediated cell signaling and cellular processes. (A) CDC7 binds to DBF4 (activated complex), which acts in initiation of DNA replication at origins by phosphorylation of MCM (mini-chromosome maintenance) proteins. (B) Upon DNA damage or stress, CDC7 phosphorylates claspin and activates ATR/CHK1 pathway. (C) CDC7 phosphorylates HP1 that promotes cohesion of sister chromatids in mitosis.
Function CDC7 is a serine-threonine kinase that participates in chromosomal DNA replication promoting progression of S phase of the cell cycle, normal chromosomal segregation during mitosis, and checkpoint response to DNA damage (Bousset and Diffley, 1998; Sawa and Masai, 2009; Takahashi et al., 2008). During DNA synthesis, CDC7 forms a complex with DBF4 (CDC7/DBF4 complex, also known as DDK), which acts in initiation of DNA replication at origins by phosphorylation of MCM (mini-chromosome maintenance) proteins (important components of replicative helicase), and allowing replisome activity (Kim et al., 2003b; Labib, 2010; Matsumoto and Masai, 2013; Sclafani and Hesselberth, 2018). Regarding chromosomal segregation, CDC7 regulates multiple proteins that enable cohesin deposition on DNA (Takahashi et al., 2008) and phosphorylates HP1 that promotes cohesion of sister chromatids in mitosis (Bailis et al., 2003). In addition, it has been described as a relevant role for CDC7 in the monopolar attachment to kinetochores during meiosis (Matos et al., 2008). In checkpoint response to DNA damage, CDC7 is important for ATR - CHK1 activation by phosphorylation of CLSPN (claspin) (Kim et al., 2008; Rainey et al., 2013; Tenca et al., 2007), which leads to inactivation of the anaphase-promoting complex (Yamada et al., 2013). It has been demonstrated that DBF4 are upstream targets of ATM or ATR, and once phosphorylated activates intra-S phase checkpoint, which suppresses DNA replication under stress (Lee et al., 2012). Under high replication stress, CDC7 may trigger apoptosis by CHK1-dependent pathway (Costanzo et al., 2003; Tsuji et al., 2008). The main cellular and molecular functions of CDC7 are illustrated in Figure 2.
Homology The CDC7 gene and protein are highly homologous among different species, as shown in Table 1.
Table 1. Comparative identity of human CDC7 with other species
% Identity for: Homo sapiens CDC7SymbolProteinDNA
vs. P.troglodytesCDC797.798.6
vs. M.mulattaCDC796.997.8
vs. C.lupusCDC790.692.9
vs. B.taurusCDC789.490.8
vs. M.musculusCdc781.483.2
vs. R.norvegicusCdc781.581.9
vs. G.gallusCDC769.874.1
vs. X.tropicaliscdc766.968.3
vs. D.reriocdc763.760.6
vs. A.gambiaeAgaP_AGAP00211040.043.8

(Source: http://www.ncbi.nlm.nih.gov/homologene)

Mutations

Somatic A total of 272 unique samples presenting CDC7 mutations were found among the 36154 tested samples reported in COSMIC (Catalogue of Somatic Mutations in Cancer; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic). The mutations p.N31Tfs*51 ([c.92del] large intestine, n=16; stomach, n=4; lung, n=1; and biliary tract, n=1) and p.L28* ([c.83T>A], liver, n=4; prostate, n=3; skin, n=3; lung, n=2; soft tissue, n=1; and glioma, n=1) were the most frequent. In agreement, 315 out of 46651 (0.7%) tested samples presented CDC7 genetic alterations (mutations, amplifications, deep deletions, and multiple alterations), as reported in cBioPortal (http://www.cbioportal.org). The distribution of somatic mutations was 122 missense substitutions, 51 truncating, 1 inframe, and 2 other mutations (a total of 176 mutated samples [0.4%]). Interestingly, p.N31Tfs*51 mutation was observed in 15 out of 176 mutations in stomach adenocarcinoma, uterine endometrioid carcinoma, colon cancer, and others. Indeed, somatic mutations in CDC7 have been reported in colorectal and gastric cancer, but its biological relevance is still poorly elucidated (Greenman et al., 2007).

Implicated in

  
Entity Adrenocortical carcinoma
Note Data mining of gene expression revealed positive regulation of genes involved in DNA damage and cell cycle pathways in samples from adrenocortical carcinoma patients, including CDC7, their higher levels were associated with worse overall survival (Subramanian and Cohen, 2019).
  
  
Entity Bladder cancer
Note In order to identify candidate genes associated with cisplatin-resistant bladder cancer cells, sensitive and cisplatin-resistant cell lines were used for microarray analysis to determine the differential expression of significant genes in resistance. A total of 18 genes, including CDC7, were significantly upregulated in cisplatin-resistant cell lines (Kim et al., 2016).
  
  
Entity Breast Cancer
Note In breast cancer, high CDC7 expression had been reported (Bonte et al., 2008; Zografos et al., 2019), and associated with the development of aggressive disease, including ERBB2 (HER2) overexpression, triple-negative subtypes, accelerated cell cycle progression, disrupted tumor differentiation, genomic instability, increased NPI score, and reduced disease-free survival (Rodriguez-Acebes et al., 2010). Using tissue microarray of a cohort of 2197 highly characterized breast carcinomas, CDC7 expression was found in 1088 samples (57%), of which 228 samples exhibited moderate or strong expression. High CDC7 levels were also related to medullary histotype, high tumor grade, estrogen receptor-negative status, high Ki67 expression; overexpression of TP53 and CDKN2A; and amplification of HER2, MYC, MDM2, CCND1, and ESR1, unfavorable tumor phenotype, and poor prognosis (Choschzick et al., 2010).
In triple negative breast cancer cellular models, the dual CDC7/CDK9 inhibitor (PHA-767491) synergizes with tyrosine kinase inhibitors to overcome resistance to EGFR -targeted therapy (McLaughlin et al., 2019): combined inhibition of EGFR and CDC7/CDK9 reduced cell proliferation accompanied by apoptosis induction, G2/M cell cycle arrest, and DNA replication inhibition.
Due to the rarity of male breast cancer (MBC), serum protein alterations have not been extensively studied. Using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time mass spectrometry (MALDI-TOF MS), a panel of differentially expressed serum proteins were identified, which included the high CDC7 expression in MBC patients (Zografos et al., 2019).
  
  
Entity Clear cell renal cell carcinoma
Note Ghatalia et al. (Ghatalia et al., 2016) analyzed the gene expression of kinases paired samples from primary and metastatic tumor tissues and found that CDC7 is more expressed in metastatic tumors. Using the Cancer Genome Atlas (TCGA) data, the authors also observed an association between high CDC7 expression and reduced metastasis-free survival (Ghatalia et al., 2016). DISEASE
  
  
Entity Cervical intraepithelial neoplasia
Note Using microarray analysis, CDC7 was found among highly expressed genes in high-grade squamous cervical intraepithelial lesions (Suman and Mishra, 2018).
  
  
Entity Colorectal cancer
Note Bonte et al. (Bonte et al., 2008) reported a high CDC7 expression in 8 of out 10 cases of colorectal cancer. In agreement, Chen et al. (Chen et al., 2013) reported a significantly higher CDC7 mRNA and protein expression in samples from 39 colorectal patients compared to their tumor-adjacent normal colorectal tissues. Analysis of 1800 colorectal carcinomas, by immunohistochemistry and tissue microarray, showed that CDC7 was highly expressed. Of note, CDC7 expression was significantly associated with TP53, suggesting that CDC7 may be a potential target in a subset of tumors with high TP53 expression (Melling et al., 2015). In contrast, loss of CDC7 expression was significantly associated with high tumor stage and grade, but was not related to nodal status. In multivariate survival analysis, strong CDC7 expression was an independent marker of improved patient survival (Melling et al., 2015).
  
  
Entity Esophageal squamous cell carcinoma
Note CDC7 is highly expressed in esophageal squamous cell carcinoma (ESCC) tissues, and that CDC7 knockdown inhibits cell proliferation, migration, and invasion, and induces apoptosis in ESCC cells. In addition, downregulation of CDC7 also partially enhances the chemosensitivity of ESCC cells to cisplatin and 5-fluorouracil, indicating that CDC7 may serve as a potential therapeutic target in ESCC (Cao and Lu, 2019).
  
  
Entity Glioblastoma
Note Inhibition of CDC7 by inhibitor PHA-767491 significantly reduced cell viability, proliferation, migration, invasion, and tumorigenesis, and induced apoptosis in glioblastoma models (Erbayraktar et al., 2016; Li et al., 2018). Li et al. (Li et al., 2018) identified that CDC7 expression was enhanced and functionally necessary for proliferation in glioblastomas, and its high expression was associated with poor prognosis.
  
  
Entity Head and neck squamous cell carcinoma
Note Human papillomavirus (HPV) is associated with a subset of head and neck squamous cell carcinoma (HNSCC) that can harbor HPV DNA and it was suggestive that there are biological and clinical differences between HPV positive (HPV +) and negative (HPV -) HNSCC. Slebos et al. (Slebos et al., 2006), comparing gene expression profiles of HPV+ and HPV- tumors, found 91 genes differentially expressed, including high CDC7 expression in HPV+ HNSCC.
  
  
Entity Hematological neoplasms
Note Hess and colleagues (Hess et al., 1998) identified the sequence of encoding human gene CDC7 and reported its overexpression in several types of cancers, including hematological neoplasms. Latterly, it was confirmed by Bont et al. (Bonte et al., 2008) in additional leukemia cellular models.
In chronic lymphocytic leukemia (CLL), CDC7 was expressed and activated in lymph node biopsies. A similar finding was also observed in an in vitro model that partially recapitulates lymph node proliferation centers of CLL. These data suggested a potential role for CDC7 in the aberrant lymph node microenvironment (Natoni et al., 2011). In addition, high CDC7 expression was associated with poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) (Hou et al., 2012b; Hou et al., 2011; Krawczyk et al., 2009). In DLBCL cell lines, CDC7 silencing combined with rituximab synergistically increased apoptosis (Hou et al., 2012a).
The dual CDC7/ CDK9 inhibitor, PHA-767491, also induced cell death on a panel of multiple myeloma cell lines and primary patient samples alone or in combination with drugs currently used in the clinics, including the TP53 mutant cells that developed resistance to dexamethasone, melphalan, and doxorubicin. PHA-767491 had the same effect on primary myeloma cells from patients who relapsed with progressive refractory disease. These data suggested that the mechanisms leading to chemoresistance in myeloma may not affect the activity of a dual CDC7/CDK9 inhibitor, thus supporting further evaluation of CDC7 and CDK9 targeting in multiple myeloma (Natoni et al., 2013).
In acute myeloid leukemia (AML), the dual CDC7/CDK9 inhibitor, PHA-767491, downregulated MCL1 and sensitized AML cell lines and primary AML blasts to BCL2 inhibitors, ABT-737 and ABT-199 (O' Reilly et al., 2018).
  
  
Entity Hepatocellular carcinoma
Note Using gene expression data sets, Zhuang et al. (Zhuang et al., 2018) detected that expression of various genes, including CDC7, was increased in hepatocellular carcinoma tissues compared to adjacent normal tissues. CDC7 overexpression was correlated with advanced histological grade and/or vascular invasion, and predicted worse overall and disease-free survival in hepatocellular carcinoma patients (Zhuang et al., 2018). It is important to highlight that the CDC7 inhibitor (PHA-767491) had a synergistic antitumor effect with 5-FU, exhibiting stronger cytotoxicity and inducing significant apoptosis in hepatocellular carcinoma cell lines and xenograft models (Li et al., 2015).
  
  
Entity Lung cancer
Note In non-small lung cancer (NSCLC) cell lines and tissue samples, CDC7 expression was highly expressed (Bonte et al., 2008). In agreement, CDC7 was significantly increased in lung adenocarcinoma tissues, as observed by immunohistochemistry and gene expression analysis in lung adenocarcinoma (Cao, 2019). In another study, high CDC7 expression significantly correlates with TP53 mutational status and predicts poor clinical outcomes in lung adenocarcinoma patients. In an experimental lung cancer model, CDC7 was also upregulated by gain-of-function mutant TP53, which induced cell cycle progression and tumorigenesis (Datta et al., 2017).
  
  
Entity Melanoma
Note CDC7 gene is located at chromosome 1p22 band, which was identified as a melanoma susceptibility locus with the high frequency of loss of heterozygosity (Walker et al., 2004). In a series of benign and dysplastic nevi, primary cutaneous melanomas and melanoma cutaneous metastasis samples, CDC7 regulatory subunits, DBF4, were found to be upregulated in malignant tissues (Nambiar et al., 2007), which was associated with shorter relapse-free survival. In the same study, DBF4 depletion reduced melanoma cell survival and proliferation (Nambiar et al., 2007). Clarke and colleagues (Clarke et al., 2009), using a tissue microarray containing 40 melanomas, 40 Spitz tumors, and 30 nevi reported that invasive melanomas and atypical Spitz nevi exhibited the highest CDC7 expression.
In order to better understand the transcriptional regulation cell cycle checkpoints in melanocytes and melanoma cell lines, Kaufmann et al. (Kaufmann et al., 2008) analyzed global gene expression patterns upon DNA damage induced by ionizing radiation, and most melanoma cell lines (11 of out 16) showed significant defects in checkpoints, which included reduced expression of TP53 transcriptional targets, and enhanced expression of proliferation-associated genes. Of note, defective melanomas at checkpoint G1 exhibited higher levels of DNA synthesis-related genes, including CDC7 and CKS1B.
Using a VSV-cDNA library and B16 melanoma tumors, CDC7 was identified (among others) as a potential immunogenic antigen for chemotherapy or immunotherapy (Zaidi et al., 2015).
  
  
Entity Oral squamous cell carcinoma
Note Evaluating CDC7 protein expression, by immunohistochemistry, in a cohort of 105 oral squamous cell carcinoma (OSCC) tumors and 30 benign oral tissues, CDC7 overexpression was found in 91% of tumor cases and 1% benign cases (Cheng et al., 2013). In multivariate analysis, CDC7 was an independent marker for overall survival in a cohort of 80 OSCC patients. In OSCC cell lines, overexpression of CDC7 inhibited genotoxin-induced apoptosis, suggesting that high CDC7 expression increases chemotherapy resistance (Cheng et al., 2013). Yong-Deok and colleagues (Yong-Deok et al., 2015) investigated the expression of inflammation-associated genes in samples from tumor and normal tissue from OSCC patients, in which genetic analysis of functional networks and ontologies identified CDC7 as one of the relevant genes. Pharmacological CDC7 inhibition with XL413 markedly reduced cell viability and proliferation by induction of apoptosis in OSCC cell lines (Jin et al., 2018).
  
  
Entity Osteosarcoma
Note In order to screen for key osteosarcoma biomarkers, Liu et al. (Liu et al., 2016) systematically screened mRNA and proteins differently expressed, and CDC7 was found as part of a gene signature for osteosarcoma.
  
  
Entity Ovarian carcinoma
Note CDC7 was a strong independent prognostic marker in epithelial ovarian carcinoma and CDC7 targeted inhibition leads to specific tumor cell death. In a cohort of 143 cases of ovarian cancer, increased levels of CDC7 protein were significantly associated with reduced tumor differentiation, advanced clinical stage, genomic instability, and accelerated cell cycle progression (Kulkarni et al., 2009). Moreover, CDC7 predicted disease-free survival, regardless of age, tumor grade and stage. CDC7 downregulation by siRNA in ovarian cancer cells (SKOV-3 and Caov-3) resulted in high levels of apoptosis (Kulkarni et al., 2009).
  
  
Entity Pancreatic cancer
Note In a cohort of 73 pancreatic adenocarcinoma patients, including 24 controls, CDC7 was highly expressed in pancreatic adenocarcinoma compared to benign pancreatic tissue, as observed by immunohistochemistry (Huggett et al., 2016). CDC7 depletion using siRNA and PHA-76749, a CDC7 small molecule inhibitor, in pancreatic cancer cellular models (Capan-1 and PANC-1), resulted in marked apoptotic cell death. Using human pancreatic cell lines (Capan-1, BxPC3, and PANC-1), the preclinical efficacy of another CDC7 inhibitor, MSK-777, was reported (induction of cell cycle arrest in G1/S and apoptosis) (Skoura et al., 2013). Taken together, these results indicated that CDC7 is a potential target and may be used as a complementary diagnosis marker to predict responses in pancreatic adenocarcinoma.
  
  
Entity Papillary thyroid carcinoma
Note Fluge et al. (Fluge et al., 2006) studied gene expression profile using cDNA microarray in papillary thyroid carcinoma samples, including 7 clinically aggressive carcinomas, 10 differentiated thyroid papillary carcinomas, and normal thyroid tissues, which were confirmed by RT-PCR, in situ hybridization and immunohistochemistry. Patients with aggressive and poorly differentiated thyroid carcinoma were specifically characterized by the marked positive regulation of several genes related to cell proliferation, including CDC7 (Fluge et al., 2006).
  
  
Entity Salivary gland tumor
Note Jaafari-Ashkavandi et al. (Jaafari-Ashkavandi et al., 2019) reported high CDC7 expression in malignant salivary gland tumors compared to pleomorphic adenomas, and its positive correlation with tumor differentiation in samples from 15 cystic adenoid carcinomas, 12 mucoepidermoid carcinomas, 14 pleomorphic adenomas, and 5 normal salivary glands (total 46 patients and donors).
  
  
Entity Uterine leiomyosarcoma
Note Barlin and colleagues (Barlin et al., 2015) compared the molecular profiles of 23 samples of uterine leiomyosarcoma (ULMS) and 29 samples of normal myometrium (NL) to identify clinically relevant molecular subtypes. Pathway analyses of genes differentially expressed between ULMS and NL samples identified over-representation of cell cycle regulation, DNA repair, and genomic integrity. External validation confirmed differential expression in 31 genes, with 84% overexpressed genes, including CDC7 and other cell cycle regulators (Barlin et al., 2015).
  

To be noted

Cdc7-deficient mice present embryonic lethality at day 3.5 (Kim et al., 2002). Mice carrying Cdc7 hypomorphic allele (Cdc7-/-tg) were born apparently normal, but smaller than their littermates. However, the rate of mortality during postnatal development was 75% within 3 days postpartum. Surviving Cdc7-/tg mice presented a normal life span and body growth retardation compared to their littermates. In addition, male and female Cdc7-/tg mice had impaired spermatogenesis and abnormal oogenesis, respectively (Kim et al., 2003a).
Promising results of CDC7 inhibition in cancer models drawn attention for the development of selective pharmacological inhibitors, among which can be mentioned 89S (Menichincheri et al., 2009), PHA-767491 (Natoni et al., 2011), 1H-pyrrolo[2,3-b]pyridine derivatives (Ermoli et al., 2009), 3-aminopyrimidine analog, pyrrolopyridinone analog, tricyclic CDC7 inhibitor, indazolylpyrimidin-2(1H)-one inhibitor, thienopyrazole-base inhibitor, 2-pyrimidyl-5-amidothiophene, imidazolone-based inhibitor (Sawa and Masai, 2009), NMS-1116354 (Colotta et al., 2010), TAK-931 (Iwai et al., 2019; Kurasawa et al., 2020), and XL413 (Koltun et al., 2012). The main cellular effects triggered by CDC7 inhibitors in the neoplasm models are: the late S-phase progression, reduced cell proliferation, DNA damage checkpoint activation, and apoptosis (Iwai et al., 2019; Kurasawa et al., 2020; Sawa and Masai, 2009). Clinical studies using CDC7 inhibitors, NMS-1116354 and TAK-931, in patients with solid tumors have been conducted, but the results of the clinical outcomes have not yet been published (https://clinicaltrials.gov/).
Acknowledgments: The authors thank Fernanda T. Udinal, from the Hemocentro Foundation of Ribeirão Preto, São Paulo, Brazil, for the English language review. This work was supported by the grant #2017/24993-0 and #2019/01700-2, São Paulo Research Foundation (FAPESP), and grant #402587/2016-2, Conselho Nacional de Desenvolvimento Cientèfico e Tecnológico (CNPq).

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Kim JM, Takemoto N, Arai K, Masai H
EMBO J 2003 Oct 1;22(19):5260-72
PMID 14517263
 
Functions of mammalian Cdc7 kinase in initiation/monitoring of DNA replication and development
Kim JM, Yamada M, Masai H
Mutat Res 2003 Nov 27;532(1-2):29-40
PMID 14643427
 
Upregulated expression of BCL2, MCM7, and CCNE1 indicate cisplatin-resistance in the set of two human bladder cancer cell lines: T24 cisplatin sensitive and T24R2 cisplatin resistant bladder cancer cell lines
Kim SH, Ho JN, Jin H, Lee SC, Lee SE, Hong SK, Lee JW, Lee ES, Byun SS
Investig Clin Urol 2016 Jan;57(1):63-72
PMID 26966728
 
Discovery of XL413, a potent and selective CDC7 inhibitor
Koltun ES, Tsuhako AL, Brown DS, Aay N, Arcalas A, Chan V, Du H, Engst S, Ferguson K, Franzini M, Galan A, Holst CR, Huang P, Kane B, Kim MH, Li J, Markby D, Mohan M, Noson K, Plonowski A, Richards SJ, Robertson S, Shaw K, Stott G, Stout TJ, Young J, Yu P, Zaharia CA, Zhang W, Zhou P, Nuss JM, Xu W, Kearney PC
Bioorg Med Chem Lett 2012 Jun 1;22(11):3727-31
PMID 22560567
 
Cdc7 kinase is a predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma
Kulkarni AA, Kingsbury SR, Tudzarova S, Hong HK, Loddo M, Rashid M, Rodriguez-Acebes S, Prevost AT, Ledermann JA, Stoeber K, Williams GH
Clin Cancer Res 2009 Apr 1;15(7):2417-25
PMID 19318489
 
Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent
Kurasawa O, Miyazaki T, Homma M, Oguro Y, Imada T, Uchiyama N, Iwai K, Yamamoto Y, Ohori M, Hara H, Sugimoto H, Iwata K, Skene R, Hoffman I, Ohashi A, Nomura T, Cho N
J Med Chem 2020 Feb 13;63(3):1084-1104
PMID 31895562
 
How do Cdc7 and cyclin-dependent kinases trigger the initiation of chromosome replication in eukaryotic cells? Genes Dev
Labib K
2010 Jun 15;24(12):1208-19 doi: 10
PMID 20551170
 
Dbf4 is direct downstream target of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) protein to regulate intra-S-phase checkpoint
Lee AY, Chiba T, Truong LN, Cheng AN, Do J, Cho MJ, Chen L, Wu X
J Biol Chem 2012 Jan 20;287(4):2531-43
PMID 22123827
 
CDC7-dependent transcriptional regulation of RAD54L is essential for tumorigenicity and radio-resistance of glioblastoma
Li Q, Xie W, Wang N, Li C, Wang M
Transl Oncol 2018 Apr;11(2):300-306
PMID 29413763
 
Dual Inhibition of Cdc7 and Cdk9 by PHA-767491 Suppresses Hepatocarcinoma Synergistically with 5-Fluorouracil
Li W, Zhao XL, Shang SQ, Shen HQ, Chen X
Curr Cancer Drug Targets 2015;15(3):196-204
PMID 25643258
 
Identification of key biomarkers involved in osteosarcoma using altered modules
Liu ZZ, Cui ST, Tang B, Wang ZZ, Luan ZX
Genet Mol Res 2016 Aug 26;15(3)
PMID 27706618
 
Dbf4-dependent CDC7 kinase links DNA replication to the segregation of homologous chromosomes in meiosis I
Matos J, Lipp JJ, Bogdanova A, Guillot S, Okaz E, Junqueira M, Shevchenko A, Zachariae W
Cell 2008 Nov 14;135(4):662-78
PMID 19013276
 
Regulation of chromosome dynamics by Hsk1/Cdc7 kinase
Matsumoto S, Masai H
Biochem Soc Trans 2013 Dec;41(6):1712-9
PMID 24256280
 
A kinase inhibitor screen identifies a dual cdc7/CDK9 inhibitor to sensitise triple-negative breast cancer to EGFR-targeted therapy
McLaughlin RP, He J, van der Noord VE, Redel J, Foekens JA, Martens JWM, Smid M, Zhang Y, van de Water B
Breast Cancer Res 2019 Jul 1;21(1):77
PMID 31262335
 
Cdc7 overexpression is an independent prognostic marker and a potential therapeutic target in colorectal cancer
Melling N, Muth J, Simon R, Bokemeyer C, Terracciano L, Sauter G, Izbicki JR, Marx AH
Diagn Pathol 2015 Jul 25;10:125
PMID 26208856
 
First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents
Menichincheri M, Bargiotti A, Berthelsen J, Bertrand JA, Bossi R, Ciavolella A, Cirla A, Cristiani C, Croci V, D'Alessio R, Fasolini M, Fiorentini F, Forte B, Isacchi A, Martina K, Molinari A, Montagnoli A, Orsini P, Orzi F, Pesenti E, Pezzetta D, Pillan A, Poggesi I, Roletto F, Scolaro A, Tatò M, Tibolla M, Valsasina B, Varasi M, Volpi D, Santocanale C, Vanotti E
2 Lead discovery
PMID 19115845
 
Identification and functional characterization of ASK/Dbf4, a novel cell survival gene in cutaneous melanoma with prognostic relevance
Nambiar S, Mirmohammadsadegh A, Hassan M, Mota R, Marini A, Alaoui A, Tannapfel A, Hegemann JH, Hengge UR
Carcinogenesis 2007 Dec;28(12):2501-10
PMID 17768177
 
Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models
Natoni A, Coyne MR, Jacobsen A, Rainey MD, O'Brien G, Healy S, Montagnoli A, Moll J, O'Dwyer M, Santocanale C
Cancers (Basel) 2013 Jul 24;5(3):901-18
PMID 24202326
 
Mechanisms of action of a dual Cdc7/Cdk9 kinase inhibitor against quiescent and proliferating CLL cells
Natoni A, Murillo LS, Kliszczak AE, Catherwood MA, Montagnoli A, Samali A, O'Dwyer M, Santocanale C
Mol Cancer Ther 2011 Sep;10(9):1624-34
PMID 21768328
 
Repression of Mcl-1 expression by the CDC7/CDK9 inhibitor PHA-767491 overcomes bone marrow stroma-mediated drug resistance in AML
O' Reilly E, Dhami SPS, Baev DV, Ortutay C, Halpin-McCormick A, Morrell R, Santocanale C, Samali A, Quinn J, O'Dwyer ME, Szegezdi E
Sci Rep 2018 Oct 25;8(1):15752
PMID 30361682
 
Cdc7-dependent and -independent phosphorylation of Claspin in the induction of the DNA replication checkpoint
Rainey MD, Harhen B, Wang GN, Murphy PV, Santocanale C
Cell Cycle 2013 May 15;12(10):1560-8
PMID 23598722
 
Targeting DNA replication before it starts: Cdc7 as a therapeutic target in p53-mutant breast cancers
Rodriguez-Acebes S, Proctor I, Loddo M, Wollenschlaeger A, Rashid M, Falzon M, Prevost AT, Sainsbury R, Stoeber K, Williams GH
Am J Pathol 2010 Oct;177(4):2034-45
PMID 20724597
 
Drug design with Cdc7 kinase: a potential novel cancer therapy target
Sawa M, Masai H
Drug Des Devel Ther 2009 Feb 6;2:255-64
PMID 19920912
 
O Cdc7 kinase where art thou? Curr Genet
Sclafani RA, Hesselberth JR
2018 Jun;64(3):677-680 doi: 10
PMID 29134273
 
Preclinical research in treatment of pancreatic cancer
Skoura E, Syrigos KN, Saif MW
JOP 2013 Jul 10;14(4):384-7
PMID 23846933
 
Gene expression differences associated with human papillomavirus status in head and neck squamous cell carcinoma
Slebos RJ, Yi Y, Ely K, Carter J, Evjen A, Zhang X, Shyr Y, Murphy BM, Cmelak AJ, Burkey BB, Netterville JL, Levy S, Yarbrough WG, Chung CH
Clin Cancer Res 2006 Feb 1;12(3 Pt 1):701-9
PMID 16467079
 
Over expression of DNA damage and cell cycle dependent proteins are associated with poor survival in patients with adrenocortical carcinoma
Subramanian C, Cohen MS
Surgery 2019 Jan;165(1):202-210
PMID 30413320
 
An interaction network driven approach for identifying biomarkers for progressing cervical intraepithelial neoplasia
Suman S, Mishra A
Sci Rep 2018 Aug 27;8(1):12927
PMID 30150654
 
Cdc7-Drf1 kinase links chromosome cohesion to the initiation of DNA replication in Xenopus egg extracts
Takahashi TS, Basu A, Bermudez V, Hurwitz J, Walter JC
Genes Dev 2008 Jul 15;22(14):1894-905
PMID 18628396
 
Cdc7 is an active kinase in human cancer cells undergoing replication stress
Tenca P, Brotherton D, Montagnoli A, Rainoldi S, Albanese C, Santocanale C
J Biol Chem 2007 Jan 5;282(1):208-15
PMID 17062569
 
The role of Dbf4/Drf1-dependent kinase Cdc7 in DNA-damage checkpoint control
Tsuji T, Lau E, Chiang GG, Jiang W
Mol Cell 2008 Dec 26;32(6):862-9
PMID 19111665
 
Deletion mapping suggests that the 1p22 melanoma susceptibility gene is a tumor suppressor localized to a 9-Mb interval
Walker GJ, Indsto JO, Sood R, Faruque MU, Hu P, Pollock PM, Duray P, Holland EA, Brown K, Kefford RF, Trent JM, Mann GJ, Hayward NK
Genes Chromosomes Cancer 2004 Sep;41(1):56-64
PMID 15236317
 
ATR-Chk1-APC/CCdh1-dependent stabilization of Cdc7-ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress
Yamada M, Watanabe K, Mistrik M, Vesela E, Protivankova I, Mailand N, Lee M, Masai H, Lukas J, Bartek J
Genes Dev 2013 Nov 15;27(22):2459-72
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Citation

This paper should be referenced as such :
Passos Vicari Hugo, Machado-Neto João Agostinho
CDC7 (cell division cycle 7)
Atlas Genet Cytogenet Oncol Haematol. 2020;24(10):358-365.
Free journal version : [ pdf ]   [ DOI ]

External links

Nomenclature
HGNC (Hugo)CDC7   1745
Cards
AtlasCDC7ID40015ch1p22
Entrez_Gene (NCBI)CDC7  8317  cell division cycle 7
AliasesCDC7L1; HsCDC7; Hsk1; huCDC7
GeneCards (Weizmann)CDC7
Ensembl hg19 (Hinxton)ENSG00000097046 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000097046 [Gene_View]  ENSG00000097046 [Sequence]  chr1:91500851-91525764 [Contig_View]  CDC7 [Vega]
ICGC DataPortalENSG00000097046
TCGA cBioPortalCDC7
AceView (NCBI)CDC7
Genatlas (Paris)CDC7
WikiGenes8317
SOURCE (Princeton)CDC7
Genetics Home Reference (NIH)CDC7
Genomic and cartography
GoldenPath hg38 (UCSC)CDC7  -     chr1:91500851-91525764 +  1p22.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CDC7  -     1p22.1   [Description]    (hg19-Feb_2009)
GoldenPathCDC7 - 1p22.1 [CytoView hg19]  CDC7 - 1p22.1 [CytoView hg38]
ImmunoBaseENSG00000097046
genome Data Viewer NCBICDC7 [Mapview hg19]  
OMIM603311   
Gene and transcription
Genbank (Entrez)AB003698 AB209337 AF005209 AF015592 AI672674
RefSeq transcript (Entrez)NM_001134419 NM_001134420 NM_003503
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CDC7
Alternative Splicing GalleryENSG00000097046
Gene ExpressionCDC7 [ NCBI-GEO ]   CDC7 [ EBI - ARRAY_EXPRESS ]   CDC7 [ SEEK ]   CDC7 [ MEM ]
Gene Expression Viewer (FireBrowse)CDC7 [ Firebrowse - Broad ]
GenevisibleExpression of CDC7 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8317
GTEX Portal (Tissue expression)CDC7
Human Protein AtlasENSG00000097046-CDC7 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO00311   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO00311  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO00311
Splice isoforms : SwissVarO00311
PhosPhoSitePlusO00311
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)Kinase-like_dom_sf    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser/Thr_kinase_AS   
Domain families : Pfam (Sanger)Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00069   
Domain families : Smart (EMBL)S_TKc (SM00220)  
Conserved Domain (NCBI)CDC7
DMDM Disease mutations8317
Blocks (Seattle)CDC7
PDB (RSDB)4F99    4F9A    4F9B    4F9C    5UWQ    5UWR   
PDB Europe4F99    4F9A    4F9B    4F9C    5UWQ    5UWR   
PDB (PDBSum)4F99    4F9A    4F9B    4F9C    5UWQ    5UWR   
PDB (IMB)4F99    4F9A    4F9B    4F9C    5UWQ    5UWR   
Structural Biology KnowledgeBase4F99    4F9A    4F9B    4F9C    5UWQ    5UWR   
SCOP (Structural Classification of Proteins)4F99    4F9A    4F9B    4F9C    5UWQ    5UWR   
CATH (Classification of proteins structures)4F99    4F9A    4F9B    4F9C    5UWQ    5UWR   
SuperfamilyO00311
Human Protein Atlas [tissue]ENSG00000097046-CDC7 [tissue]
Peptide AtlasO00311
HPRD10345
IPIIPI00448121   IPI00922848   IPI00428489   IPI01018245   IPI00642751   
Protein Interaction databases
DIP (DOE-UCLA)O00311
IntAct (EBI)O00311
BioGRIDCDC7
STRING (EMBL)CDC7
ZODIACCDC7
Ontologies - Pathways
QuickGOO00311
Ontology : AmiGOG1/S transition of mitotic cell cycle  double-strand break repair via break-induced replication  protein kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleus  nucleoplasm  nucleoplasm  cytoplasm  cytoplasm  DNA replication  positive regulation of cell proliferation  positive regulation of nuclear cell cycle DNA replication  positive regulation of G2/M transition of mitotic cell cycle  kinase activity  peptidyl-serine phosphorylation  cell cycle phase transition  intercellular bridge  metal ion binding  cell division  negative regulation of G0 to G1 transition  mitotic spindle  
Ontology : EGO-EBIG1/S transition of mitotic cell cycle  double-strand break repair via break-induced replication  protein kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleus  nucleoplasm  nucleoplasm  cytoplasm  cytoplasm  DNA replication  positive regulation of cell proliferation  positive regulation of nuclear cell cycle DNA replication  positive regulation of G2/M transition of mitotic cell cycle  kinase activity  peptidyl-serine phosphorylation  cell cycle phase transition  intercellular bridge  metal ion binding  cell division  negative regulation of G0 to G1 transition  mitotic spindle  
Pathways : KEGGCell cycle   
REACTOMEO00311 [protein]
REACTOME PathwaysR-HSA-8953750 [pathway]   
NDEx NetworkCDC7
Atlas of Cancer Signalling NetworkCDC7
Wikipedia pathwaysCDC7
Orthology - Evolution
OrthoDB8317
GeneTree (enSembl)ENSG00000097046
Phylogenetic Trees/Animal Genes : TreeFamCDC7
HOGENOMO00311
Homologs : HomoloGeneCDC7
Homology/Alignments : Family Browser (UCSC)CDC7
Gene fusions - Rearrangements
Fusion : Fusion_HubCDC7--CRM1    CDC7--LRIG1    TGFBR3--CDC7   
Fusion : QuiverCDC7
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCDC7 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CDC7
dbVarCDC7
ClinVarCDC7
MonarchCDC7
1000_GenomesCDC7 
Exome Variant ServerCDC7
GNOMAD BrowserENSG00000097046
Varsome BrowserCDC7
Genetic variants : HAPMAP8317
Genomic Variants (DGV)CDC7 [DGVbeta]
DECIPHERCDC7 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCDC7 
Mutations
ICGC Data PortalCDC7 
TCGA Data PortalCDC7 
Broad Tumor PortalCDC7
OASIS PortalCDC7 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCDC7  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DCDC7
Mutations and Diseases : HGMDCDC7
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CDC7
DgiDB (Drug Gene Interaction Database)CDC7
DoCM (Curated mutations)CDC7 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CDC7 (select a term)
intoGenCDC7
NCG6 (London) select CDC7
Cancer3DCDC7(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM603311   
Orphanet
DisGeNETCDC7
MedgenCDC7
Genetic Testing Registry CDC7
NextProtO00311 [Medical]
TSGene8317
GENETestsCDC7
Target ValidationCDC7
Huge Navigator CDC7 [HugePedia]
snp3D : Map Gene to Disease8317
BioCentury BCIQCDC7
ClinGenCDC7
Clinical trials, drugs, therapy
MyCancerGenomeCDC7
Protein Interactions : CTD8317
Pharm GKB GenePA26272
Clinical trialCDC7
Miscellaneous
canSAR (ICR)CDC7 (select the gene name)
HarmonizomeCDC7
DataMed IndexCDC7
Probes
Litterature
PubMed99 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCDC7
EVEXCDC7
GoPubMedCDC7
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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