Integrating DNA damage response and autophagy signalling axis in ultraviolet-B induced skin photo-damage: a positive association in protecting cells against genotoxic stress.

Abstract

The skin acts as both physical as well as an immunological barrier against hazardous agents from the outside environment and protects the internal organs against damage. Skin ageing is a dynamic process caused by the influence of various external factors, including damage from ultraviolet (UV-B) radiation, which is known as photo-ageing, and due to internal chronological mechanisms. A normal ageing process requires several orchestrated defense mechanisms to diverse types of stress responses, the concomitant renewal of cellular characteristics, and the homeostasis of different cell types that directly or indirectly protect the integrity of skin. Cumulative oxidative and endoplasmic reticulum (ER) stress responses and their adverse impact on biological systems in the skin are a common mechanism of the ageing process, negatively impacting DNA by causing mutations that lead to many physiological, functional, and aesthetic changes in the skin, culminating in the development of many diseases, including photo-damage and photo-carcinogenesis. Exposure of the skin to ultraviolet-(B) elicits the activation of signal transduction pathways, including DNA damage response, autophagy, and checkpoint signal adaptations associated with clearing radiation-induced DNA damage. Recent experimental reports suggest that autophagy is involved in maintaining skin homeostasis upon encountering different stresses, notably genotoxic stress. It has also been revealed that autophagy positively regulates the recognition of DNA damage by nucleotide excision repair and that skin ageing is associated with defects in the autophagy process. Moreover, autophagy is constitutively active in the skin epithelium, imparting protection to skin cells against a diverse range of outside insults, thus increasing resistance to environmental stressors. It has also been found that the stress-induced suppression of the autophagy response in experimental settings leads to enhanced apoptosis during photo-ageing upon UV-B exposure and that the maintenance of homeostasis depends on cellular autophagy levels. More recent reports in this domain claim that relieving the oxidative-stress-mediated induction of the ER stress response upon UV-B irradiation protects skin cells from photo-damage effects. The integration of autophagy and the DNA damage response under genotoxic stress is being considered as a meaningful partnership for finding novel molecular targets and devising suitable therapeutic strategies against photo-ageing disorders. Here, we summarize and review the current understanding of the mechanisms governing the intricate interplay between autophagy and the DNA damage response and its regulation by UV-B, the roles of autophagy in regulating the cellular response to UV-B-induced photodamage, and the implications of the modulation of autophagy as a meaningful partnership in the treatment and prevention of photoaging disorders.