RNA oxidation in RAS-driven cancer

ABSTRACT Chemical modifications in RNA play a crucial role in regulating gene expression in physiological and pathological conditions. One underexplored aspect of this regulation comes from reactive oxidative species (ROS), which modify nucleobases in RNA. Elevated levels of ROS and oxidative stress are prevalent in cancer cells, resulting

from metabolic reprogramming and driven by factors such as activated RAS expression. However, our understanding of how ROS-induced RNA modifications affect gene expression in a cancer context remains limited. This study aims to fill this knowledge gap by exploring the roles and regulatory implications of oxidative

modifications of RNA, with a focus on KRAS-driven redox perturbations in non-small cell lung cancer cells. The project has two main objectives. The first objective is to identify the patterns of oxidative modifications in RNA induced by oncogenic KRAS. This will be achieved through the combination of next-generation sequencing

techniques and chemical methods to create high-resolution profiles of 8-oxoguanine modifications in RNA. The second objective is to understand the molecular players that ‘read’ these modifications. This will be done through biochemical and CLIP analysis techniques, focusing on proteins from the heterogeneous nuclear

ribonucleoprotein (hnRNP) family. By elucidating these interactions, the study aims to uncover potential influences of oxidative RNA modifications on gene expression changes in cancer cells. The outcomes of this study will significantly contribute to our fundamental understanding of gene regulation in cancer. Since oxidative

stress is a hallmark of many pathological states, the technological and conceptual advancements made in this study will also have broader relevance in understanding the role of oxidative RNA modifications in the pathogenesis of diseases.