Wellman, Rachel; (2024) Investigating the relationship between UV-induced cellular damage and transcriptional remodelling of the protein homeostasis network. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Numerous stressors threaten the composition and integrity of the genome and the proteome. Cells and organisms have evolved complex, efficient and adaptable processes to respond to these threats in order to maintain viability. Classically, DNA Damage Responses (DDRs) respond to, and repair, damage to the genome, while the Proteostasis (protein homeostasis) Network (PN) corrects damage to, and disruption of, the proteome. While DDRs and the PN are essential for long-term health, some elements of the precise interplay between genotoxic and proteotoxic stress, and their associated quality control pathways, remain unknown. Furthermore, it is unknown to what extent the by-products of genotoxic stress in one cell type (e.g. microbes) can influence proteostasis within adjacent cells (e.g. host tissues). To address these questions, I have employed two distinct approaches, both of which are focused on understanding the effects of a classical genotoxic stressor, UV radiation, on proteostasis. First, I have used computational approaches to understand how human cutaneous melanoma cells (CM) remodel the PN to promote cell survival in response to UV stress-induced DNA mutations, and how this, in turn, promotes cancer. This has revealed that primary and metastatic CM samples can each be split into two distinct groups based on the expression of PN genes and that these PN clusters are predictive of survival outcomes in patients. Secondly, I have used Caenorhabditis elegans (C. elegans) proteostasis sensors to determine how UV stress in microbes can affect the integrity of the ageing proteome and the long-term health of host tissues. This has revealed that the consumption of UV-irradiated bacteria promotes the age-related failure of proteostasis in C. elegans intestinal cells. My findings raise the possibility that UV-induced genotoxic stress can act both cellautonomously, and cell-non-autonomously, to remodel the PN and negatively influence organismal health. This work expands our understanding of the relationship between genotoxic stress, the activity of the PN, and proteostasis, and reveals how this, in turn, influences long-term tissue health.

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