The DNA Damage Response as an Auxiliary Indicator of Senescence in Cancer: A User-Friendly Toolkit of Markers and...

Senescence is a cellular stress response causing a stable exit from the cell cycle. Limitation of cell proliferation is accompanied by a variety of characteristic changes, including cellular and nuclear morphological alterations, chromatin rearrangements, metabolic reprogramming, nuclear envelope rupture, and an immunomodulatory secretome, termed senescence-associated secreted phenotype (SASP). Senescence is a robust mechanism of tissue homeostasis, with crucial roles in eliminating dysfunctional and/or premalignant cells, and tissue repair. Activation of oncogenes triggers senescence, which in turn arrests DNA-damaged cells. This type of response, known as oncogene-induced senescence (OIS) is a powerful barrier to oncogenesis. However, in specific contexts, senescent cells support tumor progression, mainly via their secretome-mediated activities. The dynamic, context-dependent and ambivalent nature of senescence challenges the identification, characterization, and specific targeting of senescent cells for disease management. Importantly, senescence is highly intertwined with DNA damage response and repair (DDR/R) machinery that safeguards genome integrity. DNA damage events are frequently prevalent, while DDR/R signaling pathways are active during cellular senescence. In this regard, it can serve as an auxiliary indicator for senescent cells. In this chapter, we emphasize DDR/R as a shared hallmark of cancer and senescence. We provide a wieldy toolkit of experimental methods for monitoring DDR-related senescence markers, and we demonstrate the potential of using natural language processing to extract additional DDR/R biomarkers tailored to specific cancer types. Our methodologies can facilitate a comprehensive study of senescence in aging and cancer.