HBub1 deficiency triggers a novel p53 mediated early apoptotic checkpoint pathway in mitotic spindle damaged cells

Abstract

It has been universally believed that spindle assembly checkpoint (SAC) proteins which include the kinetochore proteins are involved in monitoring the faithful segregation of sister chromatids during cell division and hence defects in these proteins result in anueploidy. Furthermore, there are multiple sources of experimental data to suggest that a defect in p53 could also promote genomic instability leading to anueploidy. Despite these observations, a molecular basis for the prevention of aneuploidy to maintain genomic integrity upon activation of SAC has largely remained elusive. In this report, we demonstrate a novel mechanism for the maintenance of a balance between cell survival and apoptosis upon activation of SAC. We found that depletion of the outer kinetochore protein hBub1 upon activation of SAC primarily triggers early cell death mediated by p53. This phenomenon is further supported by the up-regulation of p53 down-stream pro-apoptotic genes, BAX and PUMA as well as a corresponding increase in the cleavage products of PARP and caspase 3, markers of apoptosis upon depletion of hBub1 in SAC activated cells. On the other hand, as expected, concomitant loss of both hBub1 and p53 resulted in disabling of the p53 mediated cell death pathway leading to the accumulation of cells with aneuploidy/polyploidy.Commentary also to:hBub1 negatively regulates p53 mediated early cell death upon mitotic checkpoint activationFangming Gao, Jose F Ponte, Panagiotis Papageorgis, Mary Levy, Sait Ozturk, Arthur W. Lambert, Arunthathi Thiagalingam, Hamid Mostafavi Abdolmaleky, Beth A Sullivan and Sam Thiagalingam