title: A Systems Biology Analysis of Cell Cycle Arrest Suggests that Modular Activation of Stress Responses Underlies Heterogeneous Cellular Senescence and Quiescence Phenotypes
Creators: name: Avelar, Roberto
Publisher: name: University of Liverpool Repository
Year: 2024

description: Cellular senescence (CS) and quiescence (CQ) are heterogeneous cell cycle arrest phenotypes. CS is considered irreversible, whereas CQ is reversible. Problematically, no universal markers of CS or CQ exist, and various markers for both phenotypes overlap and can be uncoupled from proliferative arrest. This has hindered our understanding of the role that CS appears to play in the development of ageing and ageing- related diseases (ARDs). In this thesis, I suggest that the heterogeneity showcased by CS and CQ phenotypes are driven by modular activation of various facets of the integrated stress response (ISR) that do not universally co-activate, resulting in heterogenous arrest biomarkers.
I present the CellAge database of senescence driver genes in Chapter 2. I show that genes capable of modulating cell cycle arrest phenotypes are involved in various ARDs and enrich for various processes, including autophagy, inflammation, apoptosis, development, repair and regeneration, alongside diverse disease terms. Indeed, CellAge genes enrich for processes that, when dysregulated, lead to all hallmarks of ageing.
In Chapter 3 I show that individual biomarkers of the senescence phenotype can be induced independently of cell cycle arrest. Furthermore, clustering of CQ and CS samples from recount3 suggests that oncogene-induced CS (OIS) is a separate programme from replicative senescence (RS) and stress- induced premature senescence (SIPS). These diverse arrest phenotypes also dysregulate different key effectors of the ISR and are significantly associated with autophagy and inflammation genes.
Chapter 4 focuses on differentially expressed genes (DEGs) in ageing and cancer. Intriguingly, both CS and CQ-associated DEGs dysregulate with age. However, CQ DEGs dysregulate in a way that suggests that quiescent cells accumulate with age – against established biological dogma – whereas CS pathways show dysregulation with age in general. I also show universal upregulation of p16 and activation of the OIS programme across 16 human cancers, whereas serum-starved CQ, contact-inhibited CQ, RS, and SIPS programmes are downregulated, suggesting that three mechanisms of cell cycle arrest exist in mammals: reversible transient and chronic CQ, and irreversible CS.
In Chapter 5 I outline a new model of arrest phenotypes as modular activation of the ISR, whereby ISR pathways – including autophagy, inflammation, and reversible and irreversible cell cycle arrest – are under control of different master regulators that can potentially be activated independently from each other. Given the widespread detection of ‘senescent’ cells in ageing and ARDs, I suggest that dysregulation of the ISR may be driving ageing and ARD phenotypes.
In summary, in this thesis I use bioinformatics methods on existing genomic datasets to advance our understanding of proliferative arrest phenotypes and how they dysregulate in ageing and ARDs. Furthermore, my model of CS and CQ induction provides a framework for understanding heterogeneous arrest phenotypes and their role in ageing and disease.