Functional screen of human MCM2–7 variant alleles for disease-causing potential

Steere, Nathan; Yamaguchi, Satoru; Andrews, Catherine A.; Nakamura, Tomoka; Shima, Naoko

doi:10.1016/j.mrfmmm.2009.03.006

Cited by 3 publications

(1 citation statement)

References 20 publications

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“…In normal human genomes, various single nucleotide polymorphisms in the mcm genes are commonly observed (http://www.ncbi.nlm.nih.gov/projects/SNP/). At least some of these polymorphisms may in themselves generate genomic instability in susceptible individuals, as at least some MCM polymorphisms cause genomic instability when assayed in budding yeast [88]. Intriguingly, among mcm cancer alleles listed in the cBioPortal (http://www.cbioportal.org), mutations that fall within the conserved ATPase motifs (Walker A and B, Sensor 1 and 2, and Arginine finger motif) commonly occur among all six Mcm genes.…”

Section: The Mcms and Cancermentioning

confidence: 99%

The Mcm2-7 Replicative Helicase: A Promising Chemotherapeutic Target

Simon

Schwacha

2014

BioMed Research International

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Numerous eukaryotic replication factors have served as chemotherapeutic targets. One replication factor that has largely escaped drug development is the Mcm2-7 replicative helicase. This heterohexameric complex forms the licensing system that assembles the replication machinery at origins during initiation, as well as the catalytic core of the CMG (Cdc45-Mcm2-7-GINS) helicase that unwinds DNA during elongation. Emerging evidence suggests that Mcm2-7 is also part of the replication checkpoint, a quality control system that monitors and responds to DNA damage. As the only replication factor required for both licensing and DNA unwinding, Mcm2-7 is a major cellular regulatory target with likely cancer relevance. Mutations in at least one of the six MCM genes are particularly prevalent in squamous cell carcinomas of the lung, head and neck, and prostrate, and MCM mutations have been shown to cause cancer in mouse models. Moreover various cellular regulatory proteins, including the Rb tumor suppressor family members, bind Mcm2-7 and inhibit its activity. As a preliminary step toward drug development, several small molecule inhibitors that target Mcm2-7 have been recently discovered. Both its structural complexity and essential role at the interface between DNA replication and its regulation make Mcm2-7 a potential chemotherapeutic target.

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Section: The Mcms and Cancermentioning

confidence: 99%

The Mcm2-7 Replicative Helicase: A Promising Chemotherapeutic Target

Simon

Schwacha

2014

BioMed Research International

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Yeast-based screening of cancer mutations in the DNA damage response protein Mre11 demonstrates importance of conserved capping domain residues

et al. 2021

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Mcm5 mutation leads to silencing of Stat1-bcl2 which accelerating apoptosis of immature T lymphocytes with DNA damage

Huang,

Liu,

et al. 2024

Preprint

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Mutation of genes involved in DNA replication continuously disrupts DNA replication and gives rise to genomic instability, which is a critical oncogenic driver. To avoid leukemia, immature T lymphocytes with genomic instability tend to undergo rapid cell death during development. However, the mechanism how immature T lymphocytes undergo rapid cell death upon genomic instability has been enigmatic. Here we showed that zebrafish mcm5 mutation leads to DNA damage in immature T lymphocytes and the immature T cells sensitively undergo rapid cell death. Detailed analyses demonstrated that the immature T lymphocytes undergo rapid apoptosis via upregulation of tp53 and downregulation of bcl2 transcription in mcm5 mutants. Mechanistically, Mcm5 directly binds to Stat1a and facilitates its phosphorylation to enhance bcl2a expression under conditions of DNA replication stress; however, in mcm5 mutants, the absence of the Mcm5-Stat1 complex decreases Stat1 phosphorylation and subsequent bcl2a transcription, accelerating apoptosis of immature T lymphocytes with genomic instability. Furthermore, our study shows that the role of Mcm5 in T-cell development is conserved in mice. In conclusion, our work identifies a role of Mcm5 in regulating T cell development via Stat1-Bcl2 cascade besides its role in DNA replication, providing a mechanism by which immature T cells with gene mutation-induced DNA damage are rapidly cleared during T lymphocyte development.

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Functional screen of human MCM2–7 variant alleles for disease-causing potential

Cited by 3 publications

References 20 publications

The Mcm2-7 Replicative Helicase: A Promising Chemotherapeutic Target

The Mcm2-7 Replicative Helicase: A Promising Chemotherapeutic Target

Yeast-based screening of cancer mutations in the DNA damage response protein Mre11 demonstrates importance of conserved capping domain residues

Mcm5 mutation leads to silencing of Stat1-bcl2 which accelerating apoptosis of immature T lymphocytes with DNA damage

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