The role of a mitotic gene expression for the function of the mitotic spindle assembly checkpoint

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The mitotic spindle assembly checkpoint controls the accurate segregation of sister chromatids during mitosis. In addition to its role to ensure chromosomal stability this signaling pathway is also essential to mediate the induction of apoptosis in response to chemotherapeutic drugs targeting the mitotic spindle. Defects in the spindle checkpoint are frequent in human cancer and can confer chromosomal instability and resistance towards chemotherapy, but the mechanisms of spindle checkpoint inactivation in cancer cells are largely unknown. Interestingly, our results show that the activity of the spindle checkpoint requires active transcription and translation during mitosis despite the fact that global gene expression is turned off. We have identified a gene and a mRNA, respectively, that participates in the spindle checkpoint, which might be subject to mitotic transcription and translation. In this research proposal we would like to identify additional genes and mRNAs that are actively expressed during a spindle checkpoint mediated mitotic arrest. Further, we want to demonstrate their mitotic expression and the physiological significance thereof. Additionally, we would like to address the molecular mechanisms of the mitotic gene expression by investigating promotor regulation and 5´-cap independent, but IRES (internal ribose entry site) dependent mRNA translation during mitosis. A deregulated mitotic gene expression might be an important mechanism of a functional inactivation of the mitotic spindle checkpoint leading to chromosomal instability and chemotherapy resistance.