Chk1 promotes replication fork progression by controlling replication initiation. 2010

Eva Petermann, and Mick Woodcock, and Thomas Helleday
Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, United Kingdom. e.petermann@bham.ac.uk

DNA replication starts at initiation sites termed replication origins. Metazoan cells contain many more potential origins than are activated (fired) during each S phase. Origin activation is controlled by the ATR checkpoint kinase and its downstream effector kinase Chk1, which suppresses origin firing in response to replication blocks and during normal S phase by inhibiting the cyclin-dependent kinase Cdk2. In addition to increased origin activation, cells deficient in Chk1 activity display reduced rates of replication fork progression. Here we investigate the causal relationship between increased origin firing and reduced replication fork progression. We use the Cdk inhibitor roscovitine or RNAi depletion of Cdc7 to inhibit origin firing in Chk1-inhibited or RNAi-depleted cells. We report that Cdk inhibition and depletion of Cdc7 can alleviate the slow replication fork speeds in Chk1-deficient cells. Our data suggest that increased replication initiation leads to slow replication fork progression and that Chk1 promotes replication fork progression during normal S phase by controlling replication origin activity.

UI MeSH Term Description Entries
D011494 Protein Kinases A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. Protein Kinase,Kinase, Protein,Kinases, Protein
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004261 DNA Replication The process by which a DNA molecule is duplicated. Autonomous Replication,Replication, Autonomous,Autonomous Replications,DNA Replications,Replication, DNA,Replications, Autonomous,Replications, DNA
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000071877 Checkpoint Kinase 1 A serine/threonine-specific protein kinase which is encoded by the CHEK1 gene in humans. Checkpoint kinase 1 (also known as Chk1) coordinates DNA damage response and cell cycle checkpoint response. Under these conditions, activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death, to prevent damaged cells from progressing through the cell cycle. Checkpoint-1 Kinase,Chk1 Kinase,Chk1 Protein Kinase,Protein Kinase, Chk1
D016196 S Phase Phase of the CELL CYCLE following G1 and preceding G2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome. S Period,Period, S,Periods, S,Phase, S,Phases, S,S Periods,S Phases
D017346 Protein Serine-Threonine Kinases A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors. Protein-Serine-Threonine Kinases,Serine-Threonine Protein Kinase,Serine-Threonine Protein Kinases,Protein-Serine Kinase,Protein-Serine-Threonine Kinase,Protein-Threonine Kinase,Serine Kinase,Serine-Threonine Kinase,Serine-Threonine Kinases,Threonine Kinase,Kinase, Protein-Serine,Kinase, Protein-Serine-Threonine,Kinase, Protein-Threonine,Kinase, Serine-Threonine,Kinases, Protein Serine-Threonine,Kinases, Protein-Serine-Threonine,Kinases, Serine-Threonine,Protein Kinase, Serine-Threonine,Protein Kinases, Serine-Threonine,Protein Serine Kinase,Protein Serine Threonine Kinase,Protein Serine Threonine Kinases,Protein Threonine Kinase,Serine Threonine Kinase,Serine Threonine Kinases,Serine Threonine Protein Kinase,Serine Threonine Protein Kinases
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D018797 Cell Cycle Proteins Proteins that control the CELL DIVISION CYCLE. This family of proteins includes a wide variety of classes, including CYCLIN-DEPENDENT KINASES, mitogen-activated kinases, CYCLINS, and PHOSPHOPROTEIN PHOSPHATASES as well as their putative substrates such as chromatin-associated proteins, CYTOSKELETAL PROTEINS, and TRANSCRIPTION FACTORS. Cell Division Cycle Proteins,Cell-Cycle Regulatory Proteins,cdc Proteins,Cell Cycle Regulatory Proteins
D034622 RNA Interference A gene silencing phenomenon whereby specific dsRNAs (RNA, DOUBLE-STRANDED) trigger the degradation of homologous mRNA (RNA, MESSENGER). The specific dsRNAs are processed into SMALL INTERFERING RNA (siRNA) which serves as a guide for cleavage of the homologous mRNA in the RNA-INDUCED SILENCING COMPLEX. DNA METHYLATION may also be triggered during this process. Gene Silencing, Post-Transcriptional,Post-Transcriptional Gene Silencing,Co-Suppression,Cosuppression,Posttranscriptional Gene Silencing,RNA Silencing,RNAi,Co Suppression,Gene Silencing, Post Transcriptional,Gene Silencing, Posttranscriptional,Gene Silencings, Posttranscriptional,Interference, RNA,Post Transcriptional Gene Silencing,Post-Transcriptional Gene Silencings,Silencing, Post-Transcriptional Gene

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