Disease relevance of CDC7

• We found that Cdc7 phosphorylates Mcm2 in at least three different sites, one of which corresponds to a site also reported to be phosphorylated by ataxia telangiectasia and Rad3-related [1].

High impact information on CDC7

• Immunoneutralization of HsCdc7-HsDbf4 activity by microinjection of anti-HsCdc7 antibodies into HeLa cells blocks initiation of DNA replication [2].
• HsDbf4 protein levels are regulated during the cell cycle with a pattern that matches that of HsCdc7 protein kinase activity [2].
• The huCdc7 protein is expressed at a constant level during the mitotic cell cycle and is localized primarily in nuclei in interphase and distributed diffusibly in cytoplasm in the mitotic phase [3].
• This finding may explain why the sequential action of cyclin-dependent and Cdc7 kinases is essential for the initiation of DNA replication [4].
• Hence, additional Cdc7 phosphorylation sites could be generated in Mcm2 by its prior phosphorylation by a cyclin-dependent kinase [4].

Biological context of CDC7

• Alanine substitution experiments with Mcm2 peptides showed that the phosphorylation of (5)S and (53)S by Cdc7 required the presence of an acidic amino acid adjacent to a serine residue [4].
• In human, ASK/hsDbf4 binds and activates huCdc7 during S phase and this kinase complex is essential for DNA replication and cell proliferation [5].
• Our results suggest that ASKL1 in a complex with Cdc7 may play a role in normal progression of both S and M phases [5].
• We report here the direct interaction of chromatin assembly factor 1 (CAF1), a key factor involved in histone deposition, with the replication kinase Cdc7-Dbf4 [6].
• Furthermore, sustained inhibition of Cdc7 in the presence of these drugs increases cell death supporting the notion that the Cdc7 kinase plays a role in maintaining cell viability during replication stress [7].

Anatomical context of CDC7

• In normal fibroblasts, however, a p53-dependent pathway actively prevents progression through a lethal S phase in the absence of sufficient Cdc7 kinase [8].
• Down-regulation of Cdc7 by small interfering RNA in a variety of tumor cell lines causes an abortive S phase, leading to cell death by either p53-independent apoptosis or aberrant mitosis [8].

Associations of CDC7 with chemical compounds

• CDC7 kinase phosphorylates serine residues adjacent to acidic amino acids in the minichromosome maintenance 2 protein [4].
• Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue [9].
• We have developed new immnunological reagents to study the properties of human Cdc7 kinase in cells challenged with the ribonucleotide reductase inhibitor hydroxyurea or with the DNA topoisomerase II inhibitor etoposide [7].
• HsCdc7 contains the conserved subdomains common to all protein-serine/threonine kinases and three "kinase inserts" that are characteristic of Cdc7p and Hsk1 [10].
• In stable transformants expressing GFP-fused full-length ASK under the tetracycline inducible promoter, GFP-ASK protein accumulates in nuclei at the telophase, but its binding to chromatin does not reach a maximum until late G1, whereas huCdc7 is imported into nuclei and binds to chromatin at early G1 [11].

Physical interactions of CDC7

• CONCLUSIONS: Nuclear localization and chromatin binding of endogenous huCdc7 and GFP-ASK expressed during the post-mitotic phase are independently regulated [11].

Enzymatic interactions of CDC7

• MCM4 and MCM6 are also phosphorylated by huCdc7 albeit to less extent [9].
• ASK forms an active kinase complex with huCdc7 that is capable of phosphorylating MCM2 protein [12].
• These results, together with the functions of Cdc7p in yeast, suggest that HsCdc7 may phosphorylate critical substrate(s) that regulate the G1/S phase transition and/or DNA replication in mammalian cells [10].

Regulatory relationships of CDC7

• Cdc7 kinase is required for DNA replication and its kinase activity is cell cycle-regulated by its activation subunit Dbf4/ASK [11].
• Cdc7 is an evolutionarily conserved kinase that regulates S phase by promoting replication origin activation [8].
• The binding of CRM1 with Cdc7 at NES2 raises an interesting possibility that CRM1 may also down-regulate Cdc7 by masking its kinase domain [13].

Other interactions of CDC7

• Furthermore, mitotic progression is retarded in ASKL1 or Cdc7 siRNA-treated cells [5].
• Conversely, CAF1 recruitment is reduced in a PCNA/DNA loading assay using Cdc7-depleted extracts [6].
• Cdc7-Dbf4 kinase is conserved through evolution and regulates initiation and progression of DNA replication [5].
• Indeed, over-expression of both huCdc7 and ASK results in the elevated phosphorylation of endogenous MCM2 protein, as manifested by appearance of the mobility-shifted form on SDS-PAGE, but does not cause any significant effects on cell cycle progression [11].
• Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells [8].

Analytical, diagnostic and therapeutic context of CDC7

• Indirect immunofluorescence staining demonstrated that HsCdc7 protein was predominantly localized in the nucleus [10].

References