Mitosis with broken chromosomes
Start date: Apr 1, 2011,
End date: Mar 31, 2015
The mechanisms that safeguard cells against aneuploidy are of great interest as aneuploidy contributes to tumorigenesis. To gain insight into these mechanisms, we studied the behavior of cells entering mitosis with damaged chromosomes. We used the endonuclease I-CreI to generate acentric chromosomes in Drosophila larvae. While I-CreI expression produces acentric chromosomes in the majority of neuronal stem cells, remarkably, it has no effect on adult survival. Our live studies reveal that acentric chromatids segregate efficiently to opposite poles. The acentric chromatid poleward movement is mediated through DNA tethers decorated with BubR1, Polo, INCENP and Aurora-B. Reduced BubR1 or Polo function results in abnormal segregation of acentric chromatids, a decrease in acentric chromosome tethering and a great reduction in adult survival. We propose that BubR1 and Polo facilitate the accurate segregation of acentric chromatids by maintaining the integrity of the tethers that connect acentric chromosomes to their centric partners. Since this is a new phenomenon, our understanding of the mechanisms of the tether-based acentric segregation and prevention of aneuploidy is limited. However, this discovery opens a new field of research and raises many exciting questions such as:Part 1. What is the structure and composition of the tether?Aim 1: Is the DSB repair machinery involved in tether formation?Aim 2: Can we identify new components required for tether formation and function?Part 2. What is the role and regulation of BubR1 on the tether? My work has revealed a novel localization and function for the conserved kinase BubR1 on the chromatin tether.Aim 3: How is BubR1 recruited to the tetherAim 4: What are the molecular pathways by which BubR1 functions on the tether?
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