Autophagy as the effector and player in DNA damage response of cells to genotoxicants

Abstract

Autophagy is a highly conserved pathway in eukaryotic cells induced by a variety of stimuli to remove superfluous or damaged organelles or abnormally aggregated proteins to maintain cellular homeostasis.A remarkable progress in our understanding of autophagy has been made in the past decade, not only regarding the molecular mechanism, but also its fundamental roles in the biological effects of various environmental stresses or the development of some human diseases. The genome of eukaryotic cells is constantly threatened by endogenous and exogenous genotoxic factors. Research in recent years has demonstrated that autophagy is not only one of the fundamental effects of genotoxicants but also a critical player in DNA damage response to genotoxic stress. A series of DNA damage response (DDR) proteins including ATM, p53, PARP-1, DNA-PKcs, TIP60, and so on have been demonstrated to play important roles in DNA damage induced autophagy, which functions as a protective measure to promote cell survival. Autophagy was also shown to play roles in the cellular responses to DNA damage, e.g. cell cycle regulation, apoptosis. Although the importance of autophagy in DDR has been recognized, there are still a lot of questions to answer. For example, how does the cell transduce the nuclei DDR signal to the cytosol to initiate autophagy; what is the mechanism of DDR related autophagy determining cell survival or cell death pathway; and what is the mechanism associating the autophagy and carcinogenesis potential of chronic low dose exposure of toxicants? In this review, we provide an overview and discuss the molecular mechanism of DNA damage induced autophagy, and their mutual regulation and its role in cell fate determination in response to genotoxic effects of environmental toxicants.1. Autophagy as a ubiquitous cellular response to environmental alterations and genotoxic stress Autophagy was described in mammalian cells more than 50 years ago as a machinery to deliver the components and organelles of the cell to lysosomes for degradation. 1 As a highly conserved ubiquitous pathway among eukaryotic cells from yeast to human, autophagy can be induced by a variety of stimuli, such as nutrient starvation, 2 growth factor withdrawal, 3 energetic deprivation, 4 oxidative stress, 5 and pathogen infection. 6-8 Many environmental toxicants have already been demonstrated to induce autophagy through the generation of endoplasmic reticulum (ER)-stress, oxidative stress, and DNA damage induction. Depending on the type of toxicant, and the exposure concentration and duration, autophagy induction could act as coordinated signaling for either death or survival determination in the processes of acute toxic response or late effects.A group of environmental metal pollutants, including cadmium, chromium, mercury, iron and arsenic, has been shown to induce autophagy. 9-13 Autophagy has been considered as the initial response of cells to metal toxicants, which may confer protection against cellular damage or act as a potential biomarker of toxic metal...

Prodigiosin-Emerged PI3K/Beclin-1-Independent Pathway Elicits Autophagic Cell Death in Doxorubicin-Sensitive and -Resistant Lung Cancer

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Bystander autophagy mediated by radiation-induced exosomal miR-7-5p in non-targeted human bronchial epithelial cells

“…Autophagy is a lysosomal degradation pathway in eukaryotic cells activated by variety of chemical and physical stresses such as ionizing radiation. There are plenty of reports demonstrating that autophagy leads to dual effects of protecting cells survival and promoting cells death under different cellular condition 28 29 . Recently, Wang et al .…”

“…Autophagy is a lysosomal degradation pathway in eukaryotic cells activated by variety of stimuli to recycle obsolete cellular components and remove the damaged proteins and organelles. Autophagy is reported to have a cytoprotective role in response to various forms of cellular stresses, including deprivation of nutrients, hypoxia and genotoxic agents, such as ionizing radiation 26 27 28 . Despite its predominant function as a potential survival mechanism, accumulating data also demonstrated that autophagy represents a pathway contributing to cell death 28 29 .…”

Proteomic Analysis Implicates Dominant Alterations of RNA Metabolism and the Proteasome Pathway in the Cellular Response to Carbon-Ion Irradiation

“…Obviously, the DNA damage response (DDR) of intricate molecular signals networks is immediately triggered after irradiation, and a series of cellular responses are evolved to counteract DNA damage and cell injury. The early cellular responses, initiated immediately and persisted for 24h or longer after irradiation, include DNA repair, cell cycle arrest, apoptosis, autophagy, etc [ 58 , 59 ]. In presented study, the proteomic expression profiles were identified 4h post-irradiation, at which time the DNA repair was still undergoing, and cell cycle arrest, cell death or survival signals could also be initiated.…”