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A role for ARHGAP35 in regulating genomic instability in NSCLC

Webber, Thomas Arthur; (2019) A role for ARHGAP35 in regulating genomic instability in NSCLC. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Genomic instability underscores intratumour heterogeneity, a prominent feature of cancer evolution that confounds treatment of cancer. Mechanisms that promote or permit increased genotypic and phenotypic diversification of tumour cells may serve to facilitate rapid evolution under strong selection pressures, such as clonal competition and therapeutic cancer treatment. In this thesis, I explore the functions of tumour suppressor driver genes mutated late during tumour evolution in NSCLC patients from the lung TRACERx study. Using a novel screening approach, I find perturbations of the DNA damage response (DDR) upon siRNA knockdown of a large number of these driver genes, not previously linked with DDR. Some of these genes were also found to disrupt tolerance to inhibition of the spindle assembly checkpoint (SAC), thus linking them to aneuploidy and CIN. DDR pathway analysis highlighted the disruptive effects of loss-of-function of those driver genes discovered in the DDR screen. Further examination one of these genes with no prior link to DDR, ARHGAP35, led to the identification of an uncharacterized link to the spliceosome, and its effect on DNA damage resolution mediated by RNA:DNA hybrids (R-loops). ARHGAP35 wasfound to affect tolerance to loss of checkpoint activity, also reflected in segregation error analysis. These observations pose interesting questions about the links between interphase damage and propagation of CIN. Altogether, the work presented here suggests that the development of function-centric biological assays is key in identifying novel features of cancer drivers and explain their mechanism of action, which may play important roles during cancer evolution

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: A role for ARHGAP35 in regulating genomic instability in NSCLC
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10083224
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