Alteration in the chromatin landscape during the DNA damage response: Continuous rotation of the gear driving cellular senescence and aging

The DNA damage response (DDR) is a crucial biological mechanism for maintaining cellular homeostasis in living organisms. This complex process involves a cascade of signaling pathways that orchestrate the sensing and processing of DNA lesions. Perturbations in this process may cause DNA repair failure, genomic instability, and irreversible cell cycle arrest, known as cellular senescence(definition), potentially culminating in tumorigenesis. Persistent DDR exerts continuous and cumulative pressure on global chromatin dynamics, resulting in altered chromatin structure and perturbed epigenetic regulations, which are highly associated with cellular senescence and aging. Sustained DDR activation and heterochromatin changes further promote senescence-associated secretory phenotype (SASP), which is responsible for aging-related diseases and cancer development. In this review, we discuss the diverse mechanisms by which DDR leads to cellular senescence and triggers SASP, together with the evidence for DDR-induced chromatin remodeling and epigenetic regulation in relation to aging.