Accurate chromosome segregation depends on the establishment of bipolar attachment, whereby sister kinetochores are attached to microtubules from opposite spindle poles. Failure of bipolar attachment will generate aneuploid cells, which directly contributes to genetic disorders, such as cancer and birth defects. Incorrect chromosome attachments are sensed by the spindle assembly checkpoint (SAC) that delays anaphase onset to allow error-correction. Once cells have established chromosome bipolar attachments, the checkpoint has to be silenced to allow anaphase onset, but little is known about the molecular mechanism for SAC silencing. The objective of this application is to uncover and characterize the SAC silencing network (SSN). We hypothesize that the SSN coordinates error sensing, error-correction, and SAC silencing to ensure chromosome bipolar attachment prior to anaphase onset. This proposal is innovative as it will uncover the poorly uncharacterized signaling cascade SSN that is critical for faithful chromosome segregation. The completion of this research will provide the first detailed view for SAC silencing process. This research will be significant because the identified new components in the SSN will uncover new targets for cancer diagnosis and prevention.
During mitosis, duplicated chromosomes segregate into two daughter cells. The segregation of sister chromatids depends on the establishment of chromosome bipolar attachment, whereby the sister kinetochores are attached by microtubules emanating from opposite spindle poles. Defect in this bipolar attachment will result in chromosome missegregation, a cause for genetic diseases, such as cancer and birth defects. This proposal aims to elucidate the mechanism that ensures chromosome bipolar attachment. Therefore, this research will potentially uncover new targets for cancer diagnosis and treatment.
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