Oxidative Stress Linked with Development of Cancer

THIRUVANANTHAPURAM:
In a ground-breaking discovery, researchers at RGCB have found relation between mRNA processing to oxidative stress response, a condition that plays a major role in the pathogenesis of many ailments, such as cancer, diabetes, and cardiovascular and neurodegenerative diseases, alongside aging. Oxidative stress, particularly, in the heart, is critical in different conditions, including hypertension, heart failure, hypoxia, ischemia-reperfusion injury, atherosclerosis, and hypertrophy (excessive development of an organ or part).

The team of researchers at Rajiv Gandhi Centre for Biotechnology (RGCB), led by Dr Rakesh S. Laishram (Scientist), Dr Feba Shaji and Dr Jamshaid Ali, noted that during oxidative stress when the production of reactive oxidative species molecules exceeds cell’s ability to neutralize, production of antioxidant protein is ramped up by increasing the fidelity of RNA processing. This research is published in the prestigious Redox Biology journal.

In the gene expression pathway, DNA is transcribed into RNA that is further translated into proteins. These proteins act as the machinery to carry out variety of cellular functions. Manipulations in these pathways through DNA, RNA or protein alter gene expression under different cellular states. One of the key pathways through which gene expression is controlled is RNA processing, which involves cleavage of the RNA. Interestingly, the process of cleavage is not always perfect or precise; rather it is has potential of multiple places where the RNA can be cut (cleavage heterogeneity).

“Controlling oxidative stress is important for keeping cells healthy and preventing human diseases. One key way cells regulate oxidative stress is by controlling gene expression through manipulations in the DNA, RNA or protein in the cell,” says the study, uncovering a critical new insight into how cells respond to oxidative stress through imprecisions of RNA processing. “This underscores therapeutic relevance of targeting cleavage precision on an RNA in mitigating oxidative stress response and associated pathologies,” Dr Laishram points out. Hailing the research paper, RGCB Director Dr Chandrabhas Narayana said it is a significant study that will help determine the vital response of antioxidants in the pathogenesis and development of a disease.

The research in the past several decades, the mechanism, regulation, or the biological implication of this cleavage imprecision was unknown. Contrary to the popular belief of being error-prone, Shaji et al., reported that this imprecision is tightly regulated to control gene expression in the cellular oxidative stress response. Key oxidative stress response genes (NQO1, HMOX1, PRDX1, and CAT) show higher heterogeneity compared to the non-stress response genes. Also, the number of cleavage sites on such RNAs are reduced to impart cellular response to oxidative stresses. Reduction in heterogeneity in cleavage site imparts tolerance to cellular oxidative stresses.

The RGCB research paper has finally elucidated that the heterogeneity is driven by the fidelity cleavage complex to cleave at the primary cleavage site under oxidative stress. This work represents the first example of a biological significance of cleavage imprecision or heterogeneity that regulates gene expression. This study shows a new cleavage imprecision-mediated anti-oxidant response that is distinct from the other pathways of oxidative stress induction. This finding will have ramifications in the understanding of disease pathogenesis, such as cardiovascular, cancer, inflammation, pathogenesis, neurodegeneration, aging, or diabetes, where the antioxidant response is critical.