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Oncogenic c-Myc induces DNA replication stress by increasing cohesins chromatin occupancy

Peripolli, Silvia; (2021) Oncogenic c-Myc induces DNA replication stress by increasing cohesins chromatin occupancy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Oncogene-induced Replication Stress (RS) has a major role in driving genomic instability and in promoting both cancer initiation and evolution. Whilst several mechanisms of oncogene-induced RS have been proposed, the exact mechanism still remains unclear. In this thesis, I investigate how the oncogene c-Myc generates RS using a c-Myc inducible cell line, and I propose a new mechanism for oncogene-induced RS. Reported mechanisms of c-Myc-induced RS are based on deregulation of DNA replication initiation events. My data suggests that these mechanisms, involving DNA over- and under-replication, and collisions between the replication and transcription machineries do not have a prominent role in generating RS in the first S-phase upon c-Myc activation. My findings support a model where increased binding of the cohesin complex to DNA in the G1-phase of the cell cycle generates RS in the following S-phase. In fact, preventing an increase in the levels of chromatin-bound cohesin by either depleting cohesin subunits or regulators partially prevents the onset of RS and DNA damage in c-Myc-activated cells. c-Myc activation leads to increased expression of the cohesin loader Mau2 and Establishment of Sister Chromatid Cohesion N-Acetyltransferase 1 (ESCO1), which respectively increase cohesin loading on the DNA and cohesin stabilisation, i.e. stable interaction of cohesins with DNA. I established by Chromatin immunoprecipitation (ChIP)-seq analysis that the cohesin complex binds preferentially to CCCTC-binding factor (CTCF) sites upon c-Myc activation. The accumulation of cohesins at these sites seems to be key in the process of c-Myc-induced RS, since depleting CTCF in c-Myc-activated cells prevents RS. Finally, I investigate whether the biological relevance of this novel mechanism of c-Myc- induced RS in cancer cell lines that display various levels of c-Myc overexpression. My data shows that depleting the loader Mau2 and the cohesin subunit Rad21 partially rescues RS in cancer cells with high levels of c-Myc overexpression, similarly to our c-Myc-inducible cell line. Since c-Myc activation is a crucial event in many human cancers, identifying the mechan- isms through which it promotes RS and genomic instability provides critical insights into cancer biology and therapy.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Oncogenic c-Myc induces DNA replication stress by increasing cohesins chromatin occupancy
Event: UCL (University College London)
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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
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
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10125895
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