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Functional Characterization of CENP-A Post-Translational Modifications in Chromosome Segregation

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Annual rept. 15 Jun 2013-14 Jun 2014

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Colorectal cancer is the second leading cause of cancer death in the United States. Approximately 85 of colorectal cancers are CIN Chromosomal instability and are associated with poor survival. The molecular mechanisms responsible for the CIN phenotype and hence means to target this pattern of genome instability remains poorly defined. I hypothesize that, post-translational modifications PTM of the centromeric nucleosome, specifically on the histone variant, CENP-A, will direct centromere activity, and that perturbations of such could lead to aneuploidy and cancer. We proposed to decipher the pathway that leads to CENP-A alpha-amino methylation and to determine the function it plays in ensuring the fidelity of chromosome segregation. We have shown here that CENP-A is methylated by NRMT1 both in vitro and in vivo. CENP-A is methylated before it is deposited into the centromere and that methylation persists throughout the cell cycle. We established that CENP-A -amino tri-methylation required for ensuring high fidelity of chromosome segregation, and hence preventing aneuploidy and cancer. Importantly, we found that loss of CENP-A alpha-amino tri-methylation trigger a proliferation advantage and cells form bigger colonies in colony formation assay. Suggesting alpha-amino tri-methylation of CENP-A is an important post-translational modification necessary for maintaining accuracy of chromosome segregation.

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  • Medicine and Medical Research

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