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Biogenesis and functions of aminocarboxypropyluridine in tRNA.

ABSTRACT: Transfer (t)RNAs contain a wide variety of post-transcriptional modifications, which play critical roles in tRNA stability and functions. 3-(3-amino-3-carboxypropyl)uridine (acp³U) is a highly conserved modification found in variable- and D-loops of tRNAs. Biogenesis and functions of acp³U have not been extensively investigated. Using a reverse-genetic approach supported by comparative genomics, we find here that the Escherichia coli yfiP gene, which we rename tapT (tRNA aminocarboxypropyltransferase), is responsible for acp³U formation in tRNA. Recombinant TapT synthesizes acp³U at position 47 of tRNAs in the presence of S-adenosylmethionine. Biochemical experiments reveal that acp³U47 confers thermal stability on tRNA. Curiously, the ?tapT strain exhibits genome instability under continuous heat stress. We also find that the human homologs of tapT, DTWD1 and DTWD2, are responsible for acp³U formation at positions 20 and 20a of tRNAs, respectively. Double knockout cells of DTWD1 and DTWD2 exhibit growth retardation, indicating that acp³U is physiologically important in mammals.

SUBMITTER: Takakura M

PROVIDER: S-EPMC6895100 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Biogenesis and functions of aminocarboxypropyluridine in tRNA.

Takakura Mayuko M Ishiguro Kensuke K Akichika Shinichiro S Miyauchi Kenjyo K Suzuki Tsutomu T

Nature communications 20191205 1

Transfer (t)RNAs contain a wide variety of post-transcriptional modifications, which play critical roles in tRNA stability and functions. 3-(3-amino-3-carboxypropyl)uridine (acp<sup>3</sup>U) is a highly conserved modification found in variable- and D-loops of tRNAs. Biogenesis and functions of acp<sup>3</sup>U have not been extensively investigated. Using a reverse-genetic approach supported by comparative genomics, we find here that the Escherichia coli yfiP gene, which we rename tapT (tRNA am ...[more]

PMID: 31804502

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Project description:Oncogenes or chemotherapy treatments trigger the induction of suppressive pathways such as apoptosis or senescence. Senescence was initially defined as a definitive arrest of cell proliferation but recent results have shown that this mechanism is also associated with cancer progression and chemotherapy resistance. Senescence is therefore much more heterogeneous than initially thought. How this response varies is not really understood, it has been proposed that its outcome relies on the secretome of senescent cells and on the maintenance of their epigenetic marks. Using experimental models of senescence escape, we now described that the stability of this proliferative arrest relies on specific tRNAs and aminoacyl-tRNA synthetases. Following chemotherapy treatment, the DNA binding of the type III RNA polymerase was reduced to prevent tRNA transcription and induce a complete cell cycle arrest. By contrast, during senescence escape, specific tRNAs such as tRNA-Leu-CAA and tRNA-Tyr-GTA were up-regulated. Reducing tRNA transcription appears necessary to control the strength of senescence since RNA pol III inhibition through BRF1 depletion maintained senescence and blocked the generation of escaping cells. mTOR inhibition also prevented chemotherapy-induced senescence escape in association with a reduction of tRNA-Leu-CAA and tRNA-Tyr-GTA expression. Further confirming the role of the tRNA-Leu-CAA and tRNA-Tyr-GTA, results showed that their corresponding tRNA ligases, LARS and YARS, were necessary for senescence escape. This effect was specific since the CARS ligase had no effect on persistence. By contrast, the down-regulation of LARS and YARS reduced the emergence of persistent cells and this was associated with the modulation of E2F1 target genes expression. Overall, these findings highlight a new regulation of tRNA biology during senescence and suggest that specific tRNAs and ligases contribute to the strength and heterogeneity of this tumor suppressive pathway.

Dataset Information

Biogenesis and functions of aminocarboxypropyluridine in tRNA.

Publications

Biogenesis and functions of aminocarboxypropyluridine in tRNA.

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