Impact of alanyl-tRNA synthetase editing deficiency in yeast.
Alanine-tRNA Ligase
/ genetics
Animals
Energy Metabolism
/ genetics
Escherichia coli
/ genetics
Gene Editing
Heat-Shock Response
/ genetics
Humans
Mice
Microcephaly
/ genetics
Neurodegenerative Diseases
/ genetics
Protein Biosynthesis
/ genetics
RNA, Transfer, Amino Acyl
/ metabolism
Saccharomyces cerevisiae
/ genetics
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
27 09 2021
27 09 2021
Historique:
accepted:
26
08
2021
revised:
19
08
2021
received:
29
06
2021
pubmed:
10
9
2021
medline:
21
12
2021
entrez:
9
9
2021
Statut:
ppublish
Résumé
Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that provide the ribosome with aminoacyl-tRNA substrates for protein synthesis. Mutations in aaRSs lead to various neurological disorders in humans. Many aaRSs utilize editing to prevent error propagation during translation. Editing defects in alanyl-tRNA synthetase (AlaRS) cause neurodegeneration and cardioproteinopathy in mice and are associated with microcephaly in human patients. The cellular impact of AlaRS editing deficiency in eukaryotes remains unclear. Here we use yeast as a model organism to systematically investigate the physiological role of AlaRS editing. Our RNA sequencing and quantitative proteomics results reveal that AlaRS editing defects surprisingly activate the general amino acid control pathway and attenuate the heatshock response. We have confirmed these results with reporter and growth assays. In addition, AlaRS editing defects downregulate carbon metabolism and attenuate protein synthesis. Supplying yeast cells with extra carbon source partially rescues the heat sensitivity caused by AlaRS editing deficiency. These findings are in stark contrast with the cellular effects caused by editing deficiency in other aaRSs. Our study therefore highlights the idiosyncratic role of AlaRS editing compared with other aaRSs and provides a model for the physiological impact caused by the lack of AlaRS editing.
Identifiants
pubmed: 34500470
pii: 6368051
doi: 10.1093/nar/gkab766
pmc: PMC8464055
doi:
Substances chimiques
RNA, Transfer, Amino Acyl
0
Alanine-tRNA Ligase
EC 6.1.1.7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
9953-9964Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM115431
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS101245
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM136213
Pays : United States
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15422-7
pubmed: 14663147
Cell. 2012 Nov 21;151(5):1042-54
pubmed: 23178123
Nature. 2008 Jan 3;451(7174):90-3
pubmed: 18172502
PLoS One. 2007 Oct 03;2(10):e996
pubmed: 17912373
Mol Cell Proteomics. 2002 Apr;1(4):323-33
pubmed: 12096114
Nature. 2006 Sep 7;443(7107):50-5
pubmed: 16906134
Science. 1991 Aug 16;253(5021):784-6
pubmed: 1876835
J Biol Chem. 2003 Nov 14;278(46):45056-61
pubmed: 12949076
Biochemistry. 2008 Nov 11;47(45):11695-703
pubmed: 18850722
Elife. 2014 Jun 02;3:
pubmed: 24891238
Nature. 2014 Jun 26;510(7506):507-11
pubmed: 24919148
Nucleic Acids Res. 2017 Apr 20;45(7):3985-3996
pubmed: 28168297
EMBO J. 2004 Nov 24;23(23):4639-48
pubmed: 15526031
Nucleic Acids Res. 1995 May 11;23(9):1481-6
pubmed: 7784200
BMC Genomics. 2018 Mar 6;19(1):184
pubmed: 29510672
Biochemistry. 1976 Jul 27;15(15):3342-6
pubmed: 182209
mBio. 2018 Jul 3;9(4):
pubmed: 29970467
Nucleic Acids Res. 2017 Apr 7;45(6):3407-3421
pubmed: 27899648
Biochim Biophys Acta Gen Subj. 2017 Nov;1861(11 Pt B):3081-3088
pubmed: 28130155
Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10260-5
pubmed: 15240874
Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9378-83
pubmed: 21606343
Hum Mutat. 2017 Oct;38(10):1348-1354
pubmed: 28493438
Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17570-5
pubmed: 25422440
DNA Repair (Amst). 2019 Sep;81:102652
pubmed: 31326363
Science. 2020 Apr 24;368(6489):
pubmed: 32327570
J Biol Chem. 2015 Apr 17;290(16):10495-503
pubmed: 25724653
Enzymes. 2020;48:69-115
pubmed: 33837712
Mol Cell Biol. 1994 Jan;14(1):606-18
pubmed: 8264629
Cold Spring Harb Perspect Biol. 2018 Jul 2;10(7):
pubmed: 29440070
Annu Rev Microbiol. 2005;59:407-50
pubmed: 16153175
Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8916-20
pubmed: 10922054
Annu Rev Biochem. 2000;69:497-529
pubmed: 10966467
Nature. 2009 Dec 10;462(7274):808-12
pubmed: 20010690
J Biol Chem. 2004 Oct 8;279(41):42359-62
pubmed: 15322138
Cold Spring Harb Symp Quant Biol. 2011;76:91-9
pubmed: 22371371
J Cell Biol. 2010 Apr 5;189(1):57-68
pubmed: 20368618
Annu Rev Microbiol. 2009;63:61-78
pubmed: 19379069
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16502-7
pubmed: 18946032
J Biol Chem. 2002 Nov 29;277(48):45729-33
pubmed: 12244062
Nat Microbiol. 2017 Aug 24;2:17117
pubmed: 28836574
Biochemistry. 2011 Mar 8;50(9):1474-82
pubmed: 21241052
FEBS Lett. 2010 Jan 21;584(2):455-9
pubmed: 19941860
Science. 2015 Jan 2;347(6217):75-8
pubmed: 25554787
Mol Cell Biol. 1995 Aug;15(8):4497-506
pubmed: 7623840
Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13348-53
pubmed: 20624963
Mol Cell. 2009 Mar 13;33(5):654-60
pubmed: 19285947
Microbiol Mol Biol Rev. 2012 Jun;76(2):115-58
pubmed: 22688810
Cell. 2000 Dec 8;103(6):877-84
pubmed: 11136973
mBio. 2019 Dec 17;10(6):
pubmed: 31848288
Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450
pubmed: 30395289
Science. 1998 Apr 24;280(5363):578-82
pubmed: 9554847
Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4028-33
pubmed: 20160114
Nucleic Acids Res. 1981 Jul 10;9(13):3105-17
pubmed: 7024910
RNA Biol. 2020 Dec 23;:1-11
pubmed: 33317386
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):72-7
pubmed: 17185419
Cell. 2009 Feb 20;136(4):746-62
pubmed: 19239893
EMBO J. 2000 May 15;19(10):2351-61
pubmed: 10811626
Mol Cell. 2002 Feb;9(2):353-62
pubmed: 11864608
Nat Commun. 2019 Apr 3;10(1):1523
pubmed: 30944313
EMBO J. 2003 Feb 3;22(3):668-75
pubmed: 12554667
PLoS One. 2012;7(12):e51551
pubmed: 23240040
Nucleic Acids Res. 2017 Jul 7;45(12):7367-7381
pubmed: 28575390
Science. 1994 Apr 8;264(5156):265-7
pubmed: 8146659
J Biol Chem. 2019 Aug 9;294(32):12191-12202
pubmed: 31239354
Nucleic Acids Res. 2020 Jul 9;48(12):6445-6457
pubmed: 32484512
Genetics. 2016 May;203(1):65-107
pubmed: 27183566