Alternative Chk1-independent S/M checkpoint in somatic cells that prevents premature mitotic entry.

Doaa Hussein Zineldeen, Noha Mohamed Shafik, Sheng Fan Li

Medical oncology (Northwood, London, England) 2017 Apr

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Genomic instability is the hallmark of cancer. Checkpoint kinase-1 (Chk1) is required for cell cycle delay after DNA damage or blocked DNA replication. Chk1-depleted tumor cells undergo premature mitosis and apoptosis. Here we analyzed the depletion of Chk1 in normal somatic cells in the absence of DNA damage in order to investigate alternative cell cycle checkpoint mechanism(s). By means of adenoviruses, flow cytometry, immunofluorescence and Western blotting, Chk1-depleted mouse embryonic fibroblasts (MEFs) were investigated. Chk1-/- MEFs arrested at the S/G2 boundary of the cell cycle with decreased protein levels of many cell cycle key players. Cyclin B1 was predominantly cytoplasmic. Interestingly, overexpression of nuclear dominant Cyclin B1 leads to nuclear translocation and premature mitosis. Chk1-/- MEFs exhibited the absence of double-strand breaks, yet cells showed delayed DNA damage recovery with pan-nuclear immunostaining pattern of Histone H2AX. Activation of this checkpoint would elicit a senescent-like phenotype. Taken together, our elaborated data revealed the existence of an additional S/M checkpoint functioning via γH2AX signaling and cytoplasmic retention of Cyclin B1 in somatic cells.

Citation

Doaa Hussein Zineldeen, Noha Mohamed Shafik, Sheng Fan Li. Alternative Chk1-independent S/M checkpoint in somatic cells that prevents premature mitotic entry. Medical oncology (Northwood, London, England). 2017 Apr;34(4):70