TRMT6/61A-dependent base methylation of tRNA-derived fragments regulates gene-silencing activity and the unfolded protein response in bladder cancer
Zhangli Su, Ida Monshaugen, Briana Wilson, Fengbin Wang, Arne Klungland, Rune Ougland, Anindya Dutta
Abstract
Abstract RNA modifications are important regulatory elements of RNA functions. However, most genome-wide mapping of RNA modifications has focused on messenger RNAs and transfer RNAs, but such datasets have been lacking for small RNAs. Here we mapped N 1 -methyladenosine (m 1 A) in the cellular small RNA space. Benchmarked with synthetic m 1 A RNAs, our workflow identified specific groups of m 1 A-containing small RNAs, which are otherwise disproportionally under-represented. In particular, 22-nucleotides long 3′ tRNA-fragments are highly enriched for TRMT6/61A-dependent m 1 A located within the seed region. TRMT6/61A-dependent m 1 A negatively affects gene silencing by tRF-3s. In urothelial carcinoma of the bladder, where TRMT6/61A is over-expressed, higher m 1 A modification on tRFs is detected, correlated with a dysregulation of tRF targetome. Lastly, TRMT6/61A regulates tRF-3 targets involved in unfolded protein response. Together, our results reveal a mechanism of regulating gene expression via base modification of small RNA.