The Genetics and Epigenetics of Centromeres in Cancer
Year: 2021
Type: dissertation
Abstract: The centromere is an essential structure required for the faithful segregation of chromosomes during mitosis, a process that is significantly dysregulated in cancer. The nucleic acid sequences that dominate the centromeric landscape are α-satellites, arrays of 171 base-pair monomer units arranged into higher-order arrays throughout the centromere. Nucleosomes that replace the canonical histone H3 with the centromeric H3 variant CENPA epigenetically mark the centromeric locus. Modern genomics and epigenomics are, however, unable to navigate the highly repetitive structure of this region, a technical shortcoming that greatly hinders the ability to study their role in human malignancy, which is the second leading cause of death globally. Methodologies aimed at characterizing centromeric sequence and function are thus needed to effectively study the genetics and molecular biology of the centromere in cancer. Our group has developed quantitative PCR assays capable of detecting chromosome-specific α-satellite sequences. This novel methodology has enabled us to study centromeres in the contexts of normal biology and human disease. We demonstrate in this thesis that centromeres undergo both genetic and epigenetic alterations in the setting of cancer. Specifically, centromeric α-satellite sequences and pericentromeric HERV-K111 retroviral sequences experience copy number reductions and sequence homogenization in neoplastic cells and tissue. Furthermore, CENPA, the H3 variant that defines centromeric chromatin, was observed to be overexpressed across multiple cancer types, with functional significance to prostate cancer phenotypes. Intriguingly, we show that overexpressed CENPA possesses a previously uncharacterized function as a putative regulator of gene transcription of important cell cycle, centromere, and kinetochore genes, through ectopic localization to their respective transcriptional start sites. Our findings collectively underscore the necessity of studying diseases of cell division (i.e. cancer) from the perspectives of centromere genetics and epigenetics. Further insight into the mechanistic underpinnings of centromere derangements in cancer will provide additional molecular context to our understanding of this fundamental structure, thus providing opportunities to therapeutically reconfigure centromeres to structurally emulate their normal conformation. Repairing the form and function of this structure that is ubiquitously important for cancer proliferation may prove to be a viable and efficacious therapeutic strategy that has pan-cancer clinical potential.
DOI: 10.7302/1341
Author: Saha, Anjan
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4287531500