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Title: Structural and mechanistic basis of mammalian Nudt12 RNA deNADding

Abstract

We recently demonstrated that mammalian cells harbor nicotinamide adenine dinucleotide (NAD)-capped messenger RNAs that are hydrolyzed by the DXO deNADding enzyme. Here, we report that the Nudix protein Nudt12 is a second mammalian deNADding enzyme structurally and mechanistically distinct from DXO and targeting different RNAs. Here, the crystal structure of mouse Nudt12 in complex with the deNADding product AMP and three Mg 2+ ions at 1.6 Å resolution provides insights into the molecular basis of the deNADding activity in the NAD pyrophosphate. Disruption of the Nudt12 gene stabilizes transfected NAD-capped RNA in cells, and its endogenous NAD-capped mRNA targets are enriched in those encoding proteins involved in cellular energetics. Furthermore, exposure of cells to nutrient or environmental stress manifests changes in NAD-capped RNA levels that are selectively responsive to Nudt12 or DXO, respectively, indicating an association of deNADding to cellular metabolism.

Authors:
 [1];  [2];  [1];  [1];  [1];  [1]; ORCiD logo [2]; ORCiD logo [1]
  1. Rutgers Univ., Piscataway, NJ (United States)
  2. Columbia Univ., New York, NY (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division; National Institutes of Health (NIH); NIH-ORIP HEI
OSTI Identifier:
1531008
Grant/Contract Number:  
[AC02-06CH11357; GM118093; S10OD012018; GM126488; P41 GM103403; S10 RR029205]
Resource Type:
Accepted Manuscript
Journal Name:
Nature Chemical Biology
Additional Journal Information:
[ Journal Volume: 15; Journal Issue: 6]; Journal ID: ISSN 1552-4450
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Enzymes; RNA; X-ray crystallography

Citation Formats

Grudzien-Nogalska, Ewa, Wu, Yixuan, Jiao, Xinfu, Cui, Huijuan, Mateyak, Maria K., Hart, Ronald P., Tong, Liang, and Kiledjian, Megerditch. Structural and mechanistic basis of mammalian Nudt12 RNA deNADding. United States: N. p., 2019. Web. doi:10.1038/s41589-019-0293-7.
Grudzien-Nogalska, Ewa, Wu, Yixuan, Jiao, Xinfu, Cui, Huijuan, Mateyak, Maria K., Hart, Ronald P., Tong, Liang, & Kiledjian, Megerditch. Structural and mechanistic basis of mammalian Nudt12 RNA deNADding. United States. doi:10.1038/s41589-019-0293-7.
Grudzien-Nogalska, Ewa, Wu, Yixuan, Jiao, Xinfu, Cui, Huijuan, Mateyak, Maria K., Hart, Ronald P., Tong, Liang, and Kiledjian, Megerditch. Fri . "Structural and mechanistic basis of mammalian Nudt12 RNA deNADding". United States. doi:10.1038/s41589-019-0293-7.
@article{osti_1531008,
title = {Structural and mechanistic basis of mammalian Nudt12 RNA deNADding},
author = {Grudzien-Nogalska, Ewa and Wu, Yixuan and Jiao, Xinfu and Cui, Huijuan and Mateyak, Maria K. and Hart, Ronald P. and Tong, Liang and Kiledjian, Megerditch},
abstractNote = {We recently demonstrated that mammalian cells harbor nicotinamide adenine dinucleotide (NAD)-capped messenger RNAs that are hydrolyzed by the DXO deNADding enzyme. Here, we report that the Nudix protein Nudt12 is a second mammalian deNADding enzyme structurally and mechanistically distinct from DXO and targeting different RNAs. Here, the crystal structure of mouse Nudt12 in complex with the deNADding product AMP and three Mg2+ ions at 1.6 Å resolution provides insights into the molecular basis of the deNADding activity in the NAD pyrophosphate. Disruption of the Nudt12 gene stabilizes transfected NAD-capped RNA in cells, and its endogenous NAD-capped mRNA targets are enriched in those encoding proteins involved in cellular energetics. Furthermore, exposure of cells to nutrient or environmental stress manifests changes in NAD-capped RNA levels that are selectively responsive to Nudt12 or DXO, respectively, indicating an association of deNADding to cellular metabolism.},
doi = {10.1038/s41589-019-0293-7},
journal = {Nature Chemical Biology},
number = [6],
volume = [15],
place = {United States},
year = {2019},
month = {5}
}

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