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PreprintCited by 10RNA and protein synthesis mechanismsRNA modifications and cancerEnzyme Structure and Function

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Biochemical and structural insights into a 5’ to 3’ RNA ligase reveal a potential role in tRNA ligation

Open access
Hu, Yingjie, Lopez, Victor A., Xu, Hengyi, Pfister, James P., Song, Bing, Servage, Kelly A., Sakurai, Masahiro, Jones, Benjamin T., Mendell, Joshua T., Wang, Tao, Wu, Jun, Lambowitz, Alan M., Tomchick, Diana R., Pawłowski, Krzysztof, Tagliabracci, Vincent S.·2024·Proceedings of the National Academy of Sciences
DOI 10.1101/2024.04.24.590974PMC PMC11071452

Preprint — published as 10.1073/pnas.2408249121

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Abstract

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here we identify C12orf29 as an atypical ATP-grasp enzyme that ligates RNA. Human C12orf29 and its homologs auto-adenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5’-phosphate and a 3’-hydroxyl. C12orf29 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro . Genetic depletion of c12orf29 in female mice alters global tRNA levels in brain. Furthermore, crystal structures of a C12orf29 homolog from Yasminevirus bound to nucleotides reveal a minimal and atypical RNA ligase fold with a unique active site architecture that participates in catalysis. Collectively, our results identify C12orf29 as an RNA ligase and suggest its involvement in tRNA biology. Significance Statement: ATP-grasp enzymes share an atypical ATP-binding fold and catalyze a diverse set of reactions involved in many essential cellular processes. We identified C12orf29 as an atypical ATP-grasp enzyme. Our biochemical and structural characterizations reveal this enzyme to be a 5’ to 3’ RNA ligase, structurally and functionally similar to the phage T4 RNA ligase. C12orf29 can ligate tRNAs in vitro and C12orf29 knockout female mice have altered tRNA levels in brain. We also report structures of C12orf29, which have revealed critical insights into the mode of ATP binding and catalysis. Our work suggests that C12orf29 may be a new player in the regulation of tRNAs.

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Metadata

Authors
Hu, Y., Lopez, V. A., Xu, H., Pfister, J. P., Song, B., Servage, K. A., Sakurai, M., Jones, B. T., Mendell, J. T., Wang, T., Wu, J., Lambowitz, A. M., Tomchick, D. R., Pawłowski, K., & Tagliabracci, V. S.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • The University of Texas at Austin (US)
  • Howard Hughes Medical Institute (US)
  • Harold C. Simmons Comprehensive Cancer Center (US)
Corresponding author
  • Hu, Yingjie
  • Lopez, Victor A.
  • Tagliabracci, Vincent S.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
openRxiv
Published
2024-04-24
Volume
121
Issue
42
ISSN
0027-8424 (ISSN-L)
DOI
10.1101/2024.04.24.590974
PMC
PMC11071452
OpenAlex
W4403298299
Cited by
10
References
1
Citations by year
2026: 3 · 2025: 6 · 2024: 1
FWCI
1.36
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion, other-oa)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • Foundation for the National Institutes of Health (R35 GM136216, DP2GM137419, R01CA282036)
  • Howard Hughes Medical Institute
  • U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, 06CH11357, DE-AC02-)
  • Welch Foundation (I‐1911, I-1961, I-2088)
  • New York Stem Cell Foundation
  • Cancer Prevention and Research Institute of Texas (RP220309, RR150033)
  • University of Texas Southwestern Medical Center
  • National Institutes of Health (DE-AC02–06CH11357)
  • National Cancer Institute (R01CA282036)
  • National Institute of General Medical Sciences (DP2GM137419, R35GM136216)
  • Biological and Environmental Research (DEAC0206CH11357)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD103627)
  • Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, 06CH11357)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
RNA ligase, anticodon loop, crystal structure

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