Environmental toxin-induced m6A RNA modification promotes R-loop accumulation and chromosomal instability

Chromosome instability (CIN) is a defining feature of cancer and a driver of tumor evolution. While genetic and epigenetic mechanisms underlying CIN are well characterized, the role of environmental carcinogens remains underexplored. Hexavalent chromium [Cr(VI)], a widespread groundwater contaminant in the United States, particularly in New Mexico, has been epidemiologically linked to increased cancer risk. Our study investigates the molecular consequences of Cr(VI) exposure in normal human colon epithelial cells, revealing a novel RNA-mediated pathway contributing to CIN. We demonstrate that Cr(VI) exposure induces epigenetic reprogramming, including the loss of repressive histone marks and disruption of heterochromatin. Notably, Cr(VI) downregulates METTL3, a key RNA N6-methyladenosine (m6A) methyltransferase, leading to reduced m6A modification and accumulation of genome-wide R-loops. Since m6A methylation is critical for R-loop resolution, its loss impairs RNA processing and genome stability. These findings suggest that Cr(VI)-induced m6A deficiency promotes R-loop persistence, thereby compromising genome integrity and facilitating CIN. Our investigation reveals a novel mechanism by which an environmental toxin induces genomic instability through RNA epigenetic dysregulation. It highlights the role of RNA modifications in genome stability and underscores the need to consider environmental exposures in cancer risk.