Functional Characterization of CENP-A Post-Translational Modifications in Chromosome Segregation
Abstract
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2014
- Accession Number
- ADA612884
Entities
People
- Sathyan K. Mattada
Organizations
- University of Virginia