Uncovering novel roles of Cyclophilin A in genome stability, cell cycle and cancers

Bedir, Marisa (2020) Uncovering novel roles of Cyclophilin A in genome stability, cell cycle and cancers. Doctoral thesis (PhD), University of Sussex.

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Abstract

Genome instability is a hallmark of cancer arising from defects in DNA repair (DNA-R) and cell cycle checkpoint networks. DNA-damaging agents are well-established cancer therapeutics that systemically increase the DNA damage burden to levels no longer conducive to viability. Therapy resistance and off-target induced morbidities are common. Therefore, better targeted and personalised treatment strategies are urgently required. Synthetic lethal (SnL) approaches exploiting cancer-specific dependencies upon specific genome stability pathways are gaining clinical relevance. Cyclophilin A (CyPA) is a peptidyl-prolyl cis-trans isomerase (PPI). CyPA inhibitors (CyPAi) are clinically established. CyPAi as a rational anti-cancer SnL strategy has not yet been advocated, although work from the O’Driscoll lab shows that CyPAi/loss or inhibition induces DNA breakage, hinders DNA-R, and impacts cell cycle progression. This thesis describes novel impacts of CyPAi and loss upon genome stability and cell cycle progression. These findings may have clinical implications for the repurposing of existing CyPAi’s as a targeted therapeutic for specific cancers. Multiple myeloma (MM) is a haematological malignancy characterised by aberrant elevated homologous recombination repair (HRR). I explore the response of MM patient-derived cell lines to CyPAi. Additionally, I describe a novel interaction between ILF2/NF45 and CyPA. ILF2 has recently been identified as a driver of recurrent, drug-resistant MM. Neuroblastoma (NB) patients with amplification of MYCN (MYCNAMP) have aggressive disease and poorer outcomes. MYCNAMP induces replication stress. I examine the response of MYCNAMP and MYCNWT NB patient-derived cell lines to CyPAi. Finally, I present data showing a role for CyPA in cell cycle progression, describing novel CyPA- interactions with key cell cycle proteins and marked disruption of G1-S and G2-M transit when CyPA function is ablated.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0447 Genes. Alleles. Genome
Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0460 Mutations
Depositing User: Library Cataloguing
Date Deposited: 03 Mar 2020 12:21
Last Modified: 21 Mar 2022 07:03
URI: http://sro.sussex.ac.uk/id/eprint/90243

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