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.

Fig. 1. Autophagy signalling. Autophagy is mainly controlled by the upstream protein kinase signalling pathways of AMPK, PI3K-I, and MAPK/ERK. Phagophore initiation is regulated by the serine/threonine protein kinase ULK1/2 complex directly and by the activity of the class III phosphatidylinositol-3-phosphate kinase (PtdIns3K) VPS34 (lipid kinase activity), which forms a complex with Beclin 1 and ATG14L. Cytoplasmic constituents are enclosed in an isolation membrane upon the initiation of the process, and elongation into a double-membraned autophagosome occurs through the action of two ubiquitin-like conjugation systems. Maturation of the autophagosome occurs upon its fusion with a lysosome to form an autolysosome, in which breakdown of the vesicle contents take place. Various kinds of stressors, such as starvation, toxins, oxidative stress, endoplasmic reticulum (ER) stress, infections, and UV-B exposure, have been found to induce the autophagy response in cells.

Fig. 2. (A) The interplay of autophagy and DNA damage response signalling. ATM/ATR signaling may either promote or inhibit autophagy, depending on the amount and extent of DNA damage. There is an optimum requirement for the induction of autophagic flux to promote DNA repair upon encountering damage, and depending upon the severity of the damage, a context-dependent autophagy response may be induced in the cell. Autophagy activation is a time-specific event following genotoxic stress. Upon genomic damage, autophagy is instantly induced (red line) in cells, which in turn induces checkpoint signalling activation (blue line), which promotes cell cycle arrest and subsequent repair of the damaged DNA. After the damage is fixed, the autophagy again declines to basal levels. Cellular senescence, on the other hand, is a delayed response and a function of time event that directly depends on the fate of the autophagic flux. Senescence is a state of durable cell cycle arrest with metabolic activities distinct from those of the proliferative state and it was originally reported to be induced by various genotoxic stressors, such as chronic UV-B response, and other factors that are intrinsic to cells, such as telomere erosion and oncogenic signaling. It is proposed to play a pivotal role in aging-related changes and as an antitumorigenic barrier, and it is thus essentially important in checkpoint activation. (B) The interplay of the unfolded protein response (UPR)-autophagy-apoptosis signalling axis. Autophagy regulates the cell survival vs. death effect in response to various stress conditions, including UV-B irradiation, by intricately balancing the unfolded protein response (UPR) and apoptotic mechanisms. UV-B irradiation of skin cells induces the oxidative-stress-mediated manifestation of endoplasmic reticulum (ER) stress, culminating in UPR, which induces autophagy. The autophagy may switch the expression of DNA damage response proteins on or off depending upon the extent of DNA damage and it regulates the expression of pro/anti-apoptotic proteins in order to maintain cellular homeostasis and in turn prevent tumorigenesis.

Sheikh Ahmad Umar

Sheikh Abdullah Tasduq