Disease relevance of CDC21

• Heterologous expression of P. carinii TS in E. coli was accomplished by cloning the coding sequence into plasmid vectors under control of the lac and tac promoters [1].
• The amino acid sequence of the yeast thymidylate synthase gene derived from the DNA sequence shows considerable homology when compared with the human, mouse, Herpesvirus saimiri, Leishmania major, Leishmania tropica, Escherichia coli, Lactobacillus casei, bacteriophage T4, and Bacillus subtilis phage phi 3T enzymes [2].
• This ORF was found to encode a polypeptide of 295 amino acid residues (33.9 kDa) that showed significant homologies to known TS of different species including mammals, plants, fungi, protozoa, bacteria, and DNA viruses [3].
• The highest amino acid homologies were found between the CIV-TS and the TS of herpesvirus ateles (54.0%), Saccharomyces cerevisiae (51.8%), herpesvirus saimiri (51.0%), rhesus monkey rhadinovirus (50.7%), mouse (50.5%), rat (50.2%), varicella-zoster virus (50.2%), equine herpesvirus 2 (50.0%), and the human TS (48.4%) [3].
• Pteroyl- and tetrahydropteroylpolyglutamate effects on the catalytic activity of thymidylate synthase from Lactobacillus leichmannii: a novel method for determining gamma-glutamyl chain lengths of the folylpolyglutamates [4].

High impact information on CDC21

• Since the temperature-sensitive mutations are recessive, the products of genes cdc8 and cdc21 must be required for both nuclear and mitochondrial DNA replication [5].
• MCBs are both necessary and sufficient for the late G1-specific transcription of the TMP1 thymidylate synthase and POL1 DNA polymerase genes [6].
• We describe here the formation in vitro of complexes on TMP1 MCBs that contain the Swi6 protein and, we suggest, a protein of relative molecular mass 120,000 (p120) that is distinct from Swi4 [6].
• We have applied this method to the DNA replication factor mcm4/cdc21, and find that chromatin association occurs during anaphase B, significantly earlier than is the case in budding yeast [7].
• This sequence has been shown to be essential for periodic expression of the POL1, CDC9, and TMP1 genes [8].

Biological context of CDC21

• The timing of this event was compared with those of CDC9 and CDC21, which are already known to be periodically transcribed, and all three genes were found to be expressed at the same time in the cell cycle [9].
• By also deleting the gene encoding thymidylate synthase (CDC21) we have constructed strains that are entirely dependent upon exogenous thymidine for viability and that can grow with normal kinetics at low thymidine concentrations [10].
• In cdc8 and cdc21, mutants defective in continued replication during the S phase of the cell cycle, mitochondrial DNA replication ceases at the nonpermissive temperature [5].
• The deduced amino acid sequence is similar to TS from other organisms and is most closely related to the enzyme from Saccharomyces cerevisiae with 65% identity [1].
• TS is found on a 330-kilobase-pair chromosome in P. carinii [1].

Associations of CDC21 with chemical compounds

• In the yeast Saccharomyces cerevisiae, the genes encoding thymidylate synthetase (CDC21) and thymidylate kinase (CDC8) are both essential for de novo TTP synthesis [11].
• 5-fluorouracil forms classic (covalent, ternary) complexes consisting of thymidylate synthase, fluoro-deoxyuridine monophosphate, and 5,10-methylene tetrahydrofolate [12].

Regulatory relationships of CDC21

• Our findings indicate that the relative expression levels of both dUTPase and uracil-DNA glycosylase can have great influence over the efficacy of thymidylate synthase-directed chemotherapy, thereby enhancing the candidacy of these proteins as prognostic markers and alternative targets for therapeutic development [13].

Other interactions of CDC21

• For the CDC21, CDC9, and POL1 genes, the Mlu I site has been shown to be absolutely required for periodic transcription [14].
• The CDC8 transcript is cell cycle regulated in yeast and is expressed coordinately with CDC9 and CDC21 at a point preceding histone transcription [9].
• Comparison of Cdc54p to related proteins from other species revealed that it closely resembles cdc21p from Schizosaccharomyces pombe [15].
• We find that during meiotic development a subset of DNA replication genes exemplified by TMP1 and RNR1 are regulated by Mbp1 [16].
• The trr1 mutations did not affect the level or periodicity of three endogenous MCB gene mRNAs (TMP1, RNR1, and SWI4) [17].

Analytical, diagnostic and therapeutic context of CDC21

• Consistent with this, immunofluorescence analysis suggests that thymidylate synthase is situated at the nuclear periphery [18].
• Northern blot hybridization reveals that the TMP 1 mRNA is a 1.15-kilobase polyadenylated transcript [2].

References