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 () and Anindya Dutta ()
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Zhangli Su: University of Alabama
Ida Monshaugen: Oslo University Hospital Rikshospitalet
Briana Wilson: University of Virginia
Fengbin Wang: University of Virginia
Arne Klungland: Oslo University Hospital Rikshospitalet
Rune Ougland: Oslo University Hospital Rikshospitalet
Anindya Dutta: University of Alabama

Nature Communications, 2022, vol. 13, issue 1, 1-17

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 N1-methyladenosine (m1A) in the cellular small RNA space. Benchmarked with synthetic m1A RNAs, our workflow identified specific groups of m1A-containing small RNAs, which are otherwise disproportionally under-represented. In particular, 22-nucleotides long 3′ tRNA-fragments are highly enriched for TRMT6/61A-dependent m1A located within the seed region. TRMT6/61A-dependent m1A negatively affects gene silencing by tRF-3s. In urothelial carcinoma of the bladder, where TRMT6/61A is over-expressed, higher m1A 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.

Date: 2022
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DOI: 10.1038/s41467-022-29790-8

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