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

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

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duospiritalis.com
.Abstract Mutation in genes involved in DNA replication continuously disrupt DNA replication and give rise to genomic instability, a critical driver of oncogenesis.To prevent leukemia, immature T lymphocytes with genomic instability often undergo rapid cell death during development.However, the mechanism by which immature T lymphocytes undergo rapid cell death upon genomic instability has been enigmatic.Here we show that zebrafish mcm5 mutation leads to DNA damage in immature T lymphocytes and the immature T cells sensitively undergo rapid cell death.
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.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 the 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 kind of mechanism by which immature T cells with gene mutation-induced DNA damage are rapidly cleared during T lymphocyte development