Kaila Nishikawa
Memorial Sloan Kettering Cancer Center
Establishing RNA Glycation as a Novel RNA Modification and Exploring its Implications in Disease
Cells employ diverse methods to regulate their response to external stimuli and to control cell fate. One of these strategies involves the dynamic adaption of biomolecules through the addition of modifications that regulate their structure, localization, and downstream functions. These modifications can be canonically installed, read, and erased enzymatically, but have also been shown to occur nonenzymatically on these same sites. Nonenzymatic modifications (NECMs) arise from spontaneous chemical reactions by reactive metabolites generated by the body or through exposure to environmental pollution, UV irradiation, or diet (including high sugar consumption), significantly impact cellular behavior by triggering signaling pathways and modifying transcriptional programming. Glycation, a NECM in which reactive sugars and their sugar metabolites covalently modify biomolecules, has recently gained attention for its ability to alter histone post-translational modification patterns, linking dysregulated metabolism to changes in cellular regulation through epigenetic mechanisms. Although primarily studied in the context of DNA and proteins, RNA glycation has also been observed in type 1 diabetes patients and is significantly associated with diabetes progression. However, tools to detect RNA glycation and understand its effect on RNA structure, function, and cellular roles are still lacking. Here, we developed and utilized novel interdisciplinary methodologies to detect RNA glycation and showed that sugars and metabolic by-products covalently react with RNA in metabolically altered cells, subsequently affecting cell fate by altering RNA translation and inducing the Ribotoxic Stress Response. We aim to establish a direct link between metabolic changes and RNA-mediated processes through epitranscriptomic reprogramming by glycation.
Cells employ diverse methods to regulate their response to external stimuli and to control cell fate. One of these strategies involves the dynamic adaption of biomolecules through the addition of modifications that regulate their structure, localization, and downstream functions. These modifications can be canonically installed, read, and erased enzymatically, but have also been shown to occur nonenzymatically on these same sites. Nonenzymatic modifications (NECMs) arise from spontaneous chemical reactions by reactive metabolites generated by the body or through exposure to environmental pollution, UV irradiation, or diet (including high sugar consumption), significantly impact cellular behavior by triggering signaling pathways and modifying transcriptional programming. Glycation, a NECM in which reactive sugars and their sugar metabolites covalently modify biomolecules, has recently gained attention for its ability to alter histone post-translational modification patterns, linking dysregulated metabolism to changes in cellular regulation through epigenetic mechanisms. Although primarily studied in the context of DNA and proteins, RNA glycation has also been observed in type 1 diabetes patients and is significantly associated with diabetes progression. However, tools to detect RNA glycation and understand its effect on RNA structure, function, and cellular roles are still lacking. Here, we developed and utilized novel interdisciplinary methodologies to detect RNA glycation and showed that sugars and metabolic by-products covalently react with RNA in metabolically altered cells, subsequently affecting cell fate by altering RNA translation and inducing the Ribotoxic Stress Response. We aim to establish a direct link between metabolic changes and RNA-mediated processes through epitranscriptomic reprogramming by glycation.
