The Human Homolog of Saccharomyces cerevisiae CDC45

Saha, Partha; Thome, Kelly C.; Yamaguchi, Ryuji; Hou, Zhi-hui; Weremowicz, Stanislawa; Dutta, Anindya

doi:10.1074/jbc.273.29.18205

Cited by 50 publications

(32 citation statements)

References 30 publications

(31 reference statements)

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“…The transcripts for CDC45 are upregulated at the G1/S transition, as has been shown in other organisms (Saha et al, 1998). Although this finding does not give an indication of the level of protein activity during the cell cycle, it indicates that CDC45 may be one of a number of genes important in the G1/S transition.…”

Section: Cdc45 In Mitosismentioning

confidence: 60%

A CDC45 Homolog in Arabidopsis Is Essential for Meiosis, as Shown by RNA Interference–Induced Gene Silencing

et al. 2003

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CDC45 is required for the initiation of DNA replication in yeast and cell proliferation in mammals and functions as a DNA polymerase ␣ loading factor in Xenopus . We have cloned a CDC45 homolog from Arabidopsis whose expression is upregulated at the G1/S transition and in young meiotic flower buds. One-third of Arabidopsis 35S : CDC45 T1 RNA interference lines are partially to completely sterile, and the proportion of sterile plants is increased by using a dmc1 promoter. T1 plants have decreased levels of the CDC45 transcript and contain 21-to 23-bp RNA fragments specific to the CDC45 gene. T2 transgenic lines, in which small RNA fragments are still present, were used to analyze S-phase entry by 5-bromodeoxyuridine incorporation, which was not altered compared with that in the wild type. However, microarray data show that other cell cycle genes are upregulated or downregulated. T2 plants also have highly reduced fertility. The severity of the phenotype is correlated with the levels of the CDC45 transcript and small RNA fragments. Severe chromosome fragmentation arising during meiosis, which is not the result of a defect in the repair of SPO11-induced double strand breaks, leads to abnormal chromosome segregation and defective pollen and ovule development.

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Section: Cdc45 In Mitosismentioning

confidence: 60%

A CDC45 Homolog in Arabidopsis Is Essential for Meiosis, as Shown by RNA Interference–Induced Gene Silencing

et al. 2003

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“…Experiments in Xenopus egg extract, budding yeast, fission yeast, and human cells have shown that loading of Pol␣-primase onto chromatin and replication origin requires Cdc45 (1,22,26,40,47). In addition to Pol␣-primase, Cdc45 also associates with ORC/Orp, RPA, Polε, and the MCM complex (21,22,34,38,39,43,47). Together, these studies suggest that Cdc45 plays a critical role in coordinating origin sequence unwinding by MCMs and initiation of DNA synthesis by Pol␣-primase.…”

mentioning

confidence: 75%

The B-Subunit of DNA Polymerase α-Primase Associates with the Origin Recognition Complex for Initiation of DNA Replication

Uchiyama

Wang

2004

Molecular and Cellular Biology

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The B-subunit (p70/Pol12p) of the DNA polymerase ␣-primase (Pol␣-primase) complex is thought to have a regulatory role in an early stage of S phase. We generated a panel of fission yeast thermosensitive mutants of the B-subunit (termed Spb70) to investigate its role in initiation of DNA replication by genetic and biochemical approaches. Here, we show that the fission yeast Spb70 genetically interacts and coprecipitates with origin recognition complex proteins Orp1/Orc1 and Orp2/Orc2 and primase coupling subunit Spp2/p58. A fraction of Spb70 associates with Orp2 on chromatin throughout the cell cycle independent of the other subunits of Pol␣-primase. Furthermore, primase Spp2/p58 subunit preferentially associates with the unphosphorylated Orp2, and the association requires Spb70. Mutations in orp2؉ that abolish or mimic the Cdc2 phosphorylation of Orp2 suppress or exacerbate the thermosensitivity of the spb70 mutants, respectively, indicating that an unphosphorylated Orp2 promotes an Spb70-dependent replication event. Together, these results indicate that the chromatin-bound B-subunit in association with origin recognition complex mediates recruiting Pol␣-primase complex onto replication origins in G 1 pre-Start through an interaction with primase Spp2/p58 subunit. Our results thus suggest a role for the recruited Pol␣-primase in the initiation of both leading and lagging strands at the replication origins.Initiation of eukaryotic chromosome replication requires the assembly of multiprotein complexes onto the chromosomal replication origins. Upon activation of the multiprotein complexes by two types of kinases, cyclin-dependent kinases (CDK) and Cdc7/Dbf4 kinase (DDK), cells transit from prereplication stage in G 1 to replication in S phase (7). A principal player in the replication complex for initiation of replication is DNA polymerase ␣-primase (Pol␣-primase). Pol␣-primase is a heterotetrameric enzyme complex, which is unique among the replicative polymerases for its ability to initiate de novo DNA synthesis of a short RNA primer on the leading and lagging strand templates by the primase activity and to extend RNA primer into a 35-nucleotide RNA-DNA primer, termed initiator DNA, by the DNA polymerase activity (6,42,44). The largest subunit of Pol␣-primase complex is of 180 kDa (p180), and it contains the DNA polymerase catalytic activity. The primase activity resides in two smaller subunits of 58 (p58) and 49 (p49) kDa. The p49 is the primase catalytic subunit that synthesizes the RNA primer. The p58 subunit is the coupling subunit of the p49 to p180 and is thought to play a role in regulating the length of RNA primer synthesis (3, 11, 37). The 70-kDa subunit, also named B-subunit, has no detectable enzymatic activity. B-subunit is essential for budding yeast (Saccharomyces cerevisiae) cell viability and has been proposed to execute a critical function in an initial stage of S phase prior to the hydroxyurea (HU) arrest point. Thus, B-subunit has been proposed to play a regulatory role in initiation of S phase ...

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“…In addition to the genes already mentioned, mammalian homologs of CDC7 and CDC45 genes have also been recently identified and shown to be expressed in a cell growth-regulated manner with a peak at the G1/S boundary (135)(136)(137)(138). While the protein level of HsCdc45 is constant throughout the cell cycle in cycling HeLa cells (138), promoter analyses have demonstrated that growth-regulated expression of the gene is essentially mediated by E2F sites in the promoter region (unpublished data).…”

Section: Regulatory Machinery For Dna Replicationmentioning

confidence: 99%

“…While the protein level of HsCdc45 is constant throughout the cell cycle in cycling HeLa cells (138), promoter analyses have demonstrated that growth-regulated expression of the gene is essentially mediated by E2F sites in the promoter region (unpublished data).…”

Section: Regulatory Machinery For Dna Replicationmentioning

confidence: 99%

Implication of transcription factor E2F in regulation of DNA replication

Ohtani¹

1999

Front Biosci

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The transcription factor E2F plays crucial roles in induction of S phase in mammalian cells by regulating the expression of genes that encode molecules involved in cell cycle progression. E2F exerts a repressive effect on E2F-responsive genes in G0/G1 phase by associating with the retinoblastoma tumor suppressor gene product pRb and the related protein p130. This repression is relieved by phosphorylation of the pRb family proteins by G1 cyclin (cyclin D and cyclin E) -dependent kinases, resulting in expression of E2F-responsive genes in late G1 with a peak at the G1/S boundary. One group of genes influenced by E2F encode cell cycle regulatory molecules, including members of the E2F family and cyclin E, demonstrating a loop-type regulation of activities of E2F and cyclin E-dependent kinase at this stage in the cell cycle. Another group is involved in DNA replication, including genes for molecules regulating initiation of DNA replication. Overexpression of E2F is sufficient to induce DNA synthesis in serum starved fibroblasts. In addition, overexpression of cyclin E, which is essential for entry into S phase, overcomes G1 arrest caused by inhibition of E2F activity without resuming E2F mediated transcription, suggesting the mergence of the two pathways. Thus, E2F target-gene products and cyclin E-dependent kinase activity apparently co-operate to initiate replication of DNA.

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The Human Homolog of Saccharomyces cerevisiae CDC45

Cited by 50 publications

References 30 publications

A CDC45 Homolog in Arabidopsis Is Essential for Meiosis, as Shown by RNA Interference–Induced Gene Silencing

A CDC45 Homolog in Arabidopsis Is Essential for Meiosis, as Shown by RNA Interference–Induced Gene Silencing

The B-Subunit of DNA Polymerase α-Primase Associates with the Origin Recognition Complex for Initiation of DNA Replication

Implication of transcription factor E2F in regulation of DNA replication

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