Abstract
Chronic cellular stress has a profound impact on the brain, leading to degeneration and accelerated aging. Recent work has revealed the vital role of RNA modifications, and the proteins responsible for regulating them, in the stress response. In our study, we defined the role of CG14618/dTrmt10A, the Drosophila counterpart of human TRMT10A a N[1]-methylguanosine methyltransferase, on m[6]A regulation and heat stress resilience in the Drosophila brain. By m[6]A-IP RNA sequencing on Drosophila head tissue, we demonstrated that manipulating dTrmt10A levels indirectly regulates m[6]A levels on polyA + RNA. dTrmt10A exerted its influence on m[6]A levels on transcripts enriched for neuronal signaling and heat stress pathways, similar to the m[6]A methyltransferase Mettl3. Intriguingly, its impact primarily targeted 3' UTR m[6]A, setting it apart from the majority of Drosophila m[6]A-modified transcripts which display 5' UTR enrichment. Upregulation of dTrmt10A led to increased resilience to acute heat stress, decreased m[6]A modification on heat shock chaperones, and coincided with decreased decay of chaperone transcripts and increased translation of chaperone proteins. Overall, these findings establish a potential mechanism by which dTrmt10A regulates the acute brain stress response through m[6]A modification.
