MCM proteins and checkpoint kinases get together at the fork

Shechter, David; Gautier, Jean

doi:10.1073/pnas.0404143101

Cited by 32 publications

(23 citation statements)

References 25 publications

(29 reference statements)

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“…The strength of the checkpoint signal generated by ATR seems to correlate with the amount of ssDNA generated by DNA damage or normal DNA replication. All of these results suggested that ATR/ATRIP coupled to MCM proteins may monitor and regulate the extent of ssDNA-replication protein A intermediates generated during normal DNA replication or after DNA damage (22). Indeed, we found that Chk1 phosphorylation was up-regulated in MCM3-overexpressed cells, which suggested that excess chromatin-bound MCM3 may stabilize the ssDNA transiently and amplify the checkpoint signal by activating ATR-Chk1 pathway.…”

Section: Discussionsupporting

confidence: 55%

Phosphorylation of MCM3 Protein by Cyclin E/Cyclin-dependent Kinase 2 (Cdk2) Regulates Its Function in Cell Cycle

Deng

Qian

et al. 2011

Journal of Biological Chemistry

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Background: Cyclin E/Cdk2 is a protein kinase in cell cycle regulation. Results: MCM3 is a novel substrate of cyclin E/Cdk2, which phosphorylates MCM3 at the site of Thr-722 and regulates its loading onto chromatin. Conclusion: Excess of MCM3 loading onto DNA will activate the checkpoint pathway. Significance: We revealed the novel role of MCM3 regulated by cyclin E/Cdk2 in controlling the S phase checkpoint.

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Section: Discussionsupporting

confidence: 55%

Phosphorylation of MCM3 Protein by Cyclin E/Cyclin-dependent Kinase 2 (Cdk2) Regulates Its Function in Cell Cycle

Deng

Qian

et al. 2011

Journal of Biological Chemistry

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“…Interestingly, MCM2 and MCM3 are phosphorylated by ATR (ataxia-telangiectasia-mutated-and Rad3-related) and ataxia-telangiectasia-mutated, respectively, whereas MCM7 interacts with Rad3-related-interacting protein in checkpoint activation for DNA damage response (Cortez et al, 2004). These MCM modifications by ataxia-telangiectasia-mutated and Rad3-related might have functions unrelated to origin firing in DNA replication licensing as the phosphorylated MCMs are both chromatin-bound and in the cytosol (Shechter and Gautier, 2004). Our finding of specific overexpression of MCM2, MCM3 and MCM7, but not the others, in MB may imply the significances of this DNA damage checkpoint and ataxia-telangiectasia-mutated/Rad3-related-mediated phosphorylations of MCMs in MB tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion

et al. 2010

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Minichromosome maintenance (MCM) proteins 2-7 are important in DNA replication licensing. Functional roles beyond licensing are speculated. In addition, significances in medulloblastoma (MB) remain unclear. In this study, we showed the frequent deregulation of MCM2 and MCM3 expression in 7 MB cell lines and 31 clinical samples. Moreover, DAOY and ONS76 and the clinical samples expressed elevated MCM7 transcripts with genomic gain of the gene. Immunopositivity restricted to tumor cells was found in 41, 37 and 53 out of 73 MB cases for MCM2, MCM3 and MCM7, respectively. High-MCM3 expression was associated with poor prognosis. Knockdowns of these MCMs significantly inhibited anchorage-dependent and -independent MB cell growth. The inhibition of MCM3 expression by small interfering RNA knockdown was related to G1 arrest with reduced cyclin A expression, whereas the MCM2-and MCM7-knocked-down cells arrested at G2/M with increased cyclin A expression. Interestingly, we demonstrated the links of these MCMs with cell migration and invasion using wound-healing and Transwell migration/invasion assays. Exogenous overexpression of MCM2, MCM3 and MCM7 increased anchorage-independent cell growth, and also cell migration and invasion capabilities in MB cells. The knockdown reduced the number of filopodial cells and the cells with intense stress fibers by blocking cdc42 and Rho activation. Taken together, deregulation of MCM2, MCM3 and MCM7 expression might be involved in MB tumorigenesis and we revealed undefined roles of these MCMs in control of MB cell migration and invasion.

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“…Replication forks are routinely arrested by a broad variety of stresses (Hyrien, 2000;Shechter and Gautier, 2004). The relationships between homologous recombination (HR) and DNA replication have been well documented in cells challenged with strong genotoxic stresses.…”

Section: Introductionmentioning

confidence: 99%

A homologous recombination defect affects replication-fork progression in mammalian cells

Daboussi

Courbet

Benhamou

et al. 2008

Journal of Cell Science

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Faithful genome transmission requires a network of pathways coordinating DNA replication to DNA repair and recombination. Here, we used molecular combing to measure the impact of homologous recombination (HR) on the velocity of DNA replication forks. We used three hamster cell lines defective in HR either by overexpression of a RAD51 dominant-negative form, or by a defect in the RAD51 paralogue XRCC2 or the breast tumor suppressor BRCA2. Irrespectively of the type or extent of HR alteration, all three cell lines exhibited a similar reduction in the rate of replication-fork progression, associated with an increase in the density of replication forks. Importantly, this phenotype was completely reversed in complemented derivatives of Xrcc2 and Brca2 mutants. These data reveal a novel role for HR, different from the reactivation of stalled replication forks, which may play an important role in genome stability and thus in tumor protection.

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MCM proteins and checkpoint kinases get together at the fork

Cited by 32 publications

References 25 publications

Phosphorylation of MCM3 Protein by Cyclin E/Cyclin-dependent Kinase 2 (Cdk2) Regulates Its Function in Cell Cycle

Phosphorylation of MCM3 Protein by Cyclin E/Cyclin-dependent Kinase 2 (Cdk2) Regulates Its Function in Cell Cycle

Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion

A homologous recombination defect affects replication-fork progression in mammalian cells

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