Etd

Defining the mechanisms contributing to genomic instability following RB loss

Public Deposited

Downloadable Content

open in viewer

The vast majority of human cancers exhibit loss or functional inactivation of the retinoblastoma protein. For over 30 years studies have descried the canonical role of RB in controlling the G1-to-S transition through the binding and regulation of E2F transcription factors. While previous work has shown the loss of RB results in of genomic instability, mechanistic insights into the underlying defects arising from this loss of RB have yet to be understood. Here I asses the role RB loss in the acquisition of DNA damage in RPE-1 cells during mitosis. I show that loss of RB leads to increased DNA damage in mitosis and that damage is occurring at centromeres. Furthermore, the damage seen during mitosis can be decreased by increasing key components of chromatin, Cohesin and Condensin. Finally, the changes to chromatin structure resulting from loss of RB lead to increased rates of transcription promoting increased levels of centromeric Aurora B and DNA damage. In cancer cells we also see increased centromeric Aurora B levels resulting in the loss of microtubule stability and generation of segregation errors. This persistent loss or gain of whole chromosomes is known as nCIN and has been shown to promote intra-tumor heterogeneity and drug resistance. In non small cell lung cancer cells, we show that chromosome segregation errors are sensitive to changes in microtubule dynamics and through increasing chromosome cohesion we are able to suppress nCIN and reduce intra-tumor heterogeneity. Suppression of nCIN was subsequently found to reduce the incidence of acquired drug resistance. These findings suggest mechanisms to suppress nCIN in RB deficient cancers may allow us to develop more effective therapeutic treatments.

Creator
Contributors
Degree
Unit
Publisher
Identifier
  • etd-82106
Keyword
Advisor
Orcid
Committee
Defense date
Year
  • 2022
Date created
  • 2022-12-06
Resource type
Source
  • etd-82106
Rights statement
Last modified
  • 2023-09-19

Relations

In Collection:

Items

Items

Permanent link to this page: https://digital.wpi.edu/show/3197xq25x