Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

Abstract

There has been enormous recent progress in understanding how human cells respond to oxidative stress, such as that caused by exposure to ionizing radiation. We have witnessed a significant deciphering of the events that underlie how antioxidant responses counter pro-oxidant damage to key biological targets in all cellular compartments, including the genome and mitochondria. These cytoprotective responses include: 1. The basal cellular repertoire of antioxidant capabilities and its supporting cast of facilitator enzymes; and 2. The inducible phase of the antioxidant response, notably that mediated by the Nrf2 transcription factor. There has also been frenetic progress in defining how reactive electrophilic species swamp existing protective mechanisms to augment DNA damage, events that are embodied in the cellular “DNA-damage response”, including cell cycle checkpoint activation and DNA repair, which occur on a time scale of hours to days, as well as the implementation of cellular responses such as apoptosis, autophagy, senescence and reprograming that extend the time period of damage sensing and response into weeks, months and years. It has become apparent that, in addition to the initial oxidative insult, cells typically undergo further waves of secondary reactive oxygen/nitrogen species generation, DNA damage and signaling and that these may reemerge long after the initial events have subsided, probably being driven, at least in part, by persisting DNA damage. These reactive oxygen/nitrogen species are an integral part of the pathological consequences of radiation exposure and may persist across multiple cell divisions. Because of the pervasive nature of oxidative stress, a cell will manifest different responses in different subcellular compartments and to different levels of stress injury. Aspects of these compartmentalized responses can involve the same proteins (such as ATM, p53 and p21) but in different functional guises, e.g., in cytoplasmic versus nuclear responses or in early-versus late-phase events. Many of these responses involve gene activation and new protein synthesis as well as a plethora of post-translational modifications of both basal and induced response proteins. It is these responses that we focus on in this review.

Time‐Dependent Measurement of Nrf2‐Regulated Antioxidant Response to Ionizing Radiation Toward Identifying Potential Protein Biomarkers for Acute Radiation Injury

“…For these, a nadir was seen at either 8 or 24 h for most mouse groups (Figure ), which is in keeping with the findings of the Romeo group . This biphasic theme that emerged may reflect early and late radiation responses controlled by different mechanisms . Cellular responses to radiation are multifaceted and persisting.…”

“…Besides catalase, glutathione peroxidases (GPX) also detoxify H 2 O 2 , and the relative contribution of CAT and GPX to H 2 O 2 removal is cell type and tissue dependent . The relationships between these antioxidants is further complicated by induction of SOD1 through pro‐inflammatory pathways that could be involved in our experiments …”

“…The report proposed a mechanism of posttranslational activation whereby an increased proportion of GCL in the holoenzyme form compared to the inactive monomeric form results in high activity and GSH production . Another interpretation is that the high level of damage switches the redox rheostat toward a pro‐oxidant inflammatory response . This second interpretation would suggest that this enzyme would be an ideal biomarker for assessing damage, and mitigators aimed at increasing its expression would be of value.…”

“…Besides potent induction of Nrf2 after IR, studies also indicated different induction kinetics in different cell types . For example, in the two initial reports, Tsukimoto et al.…”

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

“…These encode proteins involved in activities such as the early activation of various DNA repair pathways and transient cell cycle checkpoints as well in later events, e.g., proapoptotic genes/proteins such as BAX (BCL-2-associated X) and PUMA (p53 upregulated modulator of apoptosis). p53 can also favor apoptosis by downregulating antiapoptotic proteins such as survivin and BCL-2 (B-cell lymphoma 2) [38,39]. Another p53-regulated gene, CDKN1A, encodes the p21 WAF1 (henceforth, p21) protein, which plays key roles in both early and late responses to DNA damage, such as in the transient activation of cell cycle checkpoints and in the sustained growth arrest (cytostasis/dormancy) seen in many cell types [3,39,40].…”