PMID- 33380464
OWN - NLM
STAT- MEDLINE
DCOM- 20210421
LR  - 20220402
IS  - 1469-9001 (Electronic)
IS  - 1355-8382 (Print)
IS  - 1355-8382 (Linking)
VI  - 27
IP  - 4
DP  - 2021 Apr
TI  - Disease-associated mutations in mitochondrial precursor tRNAs affect binding, 
      m1R9 methylation, and tRNA processing by mtRNase P.
PG  - 420-432
LID - 10.1261/rna.077198.120 [doi]
AB  - Mitochondrial diseases linked to mutations in mitochondrial (mt) tRNA sequences 
      are common. However, the contributions of these tRNA mutations to the development 
      of diseases is mostly unknown. Mutations may affect interactions with (mt)tRNA 
      maturation enzymes or protein synthesis machinery leading to mitochondrial 
      dysfunction. In human mitochondria, in most cases the first step of tRNA 
      processing is the removal of the 5' leader of precursor tRNAs (pre-tRNA) 
      catalyzed by the three-component enzyme, mtRNase P. Additionally, one component 
      of mtRNase P, mitochondrial RNase P protein 1 (MRPP1), catalyzes methylation of 
      the R9 base in pre-tRNAs. Despite the central role of 5' end processing in 
      mitochondrial tRNA maturation, the link between mtRNase P and diseases is mostly 
      unexplored. Here, we investigate how 11 different human disease-linked mutations 
      in (mt)pre-tRNA(Ile), (mt)pre-tRNA(Leu(UUR)), and (mt)pre-tRNA(Met) affect the 
      activities of mtRNase P. We find that several mutations weaken the pre-tRNA 
      binding affinity (K(D) s are approximately two- to sixfold higher than that of 
      wild-type), while the majority of mutations decrease 5' end processing and 
      methylation activity catalyzed by mtRNase P (up to  approximately 55% and 90% reduction, 
      respectively). Furthermore, all of the investigated mutations in 
      (mt)pre-tRNA(Leu(UUR)) alter the tRNA fold which contributes to the partial loss 
      of function of mtRNase P. Overall, these results reveal an etiological link 
      between early steps of (mt)tRNA-substrate processing and mitochondrial disease.
CI  - (c) 2021 Karasik et al.; Published by Cold Spring Harbor Laboratory Press for the 
      RNA Society.
FAU - Karasik, Agnes
AU  - Karasik A
AD  - Department of Biochemistry and Molecular Biology, Uniformed Services University 
      of the Health Sciences, Bethesda, Maryland 20814, USA.
FAU - Wilhelm, Catherine A
AU  - Wilhelm CA
AD  - Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
FAU - Fierke, Carol A
AU  - Fierke CA
AD  - Department of Chemistry, Department of Biological Chemistry, University of 
      Michigan, Ann Arbor, Michigan 48109, USA.
AD  - Department of Chemistry, Department of Biochemistry and Biophysics, Texas A&M 
      University, College Station, Texas 77843, USA.
FAU - Koutmos, Markos
AU  - Koutmos M
AD  - Department of Chemistry, Program in Biophysics, University of Michigan, Ann 
      Arbor, Michigan 48109, USA.
LA  - eng
GR  - R01 GM055387/GM/NIGMS NIH HHS/United States
GR  - R01 GM117141/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20201230
PL  - United States
TA  - RNA
JT  - RNA (New York, N.Y.)
JID - 9509184
RN  - 0 (RNA Precursors)
RN  - 0 (RNA, Mitochondrial)
RN  - 9014-25-9 (RNA, Transfer)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.- (TRMT10c protein, human)
SB  - IM
MH  - Base Pairing
MH  - Base Sequence
MH  - Humans
MH  - Methylation
MH  - Methyltransferases/*chemistry/genetics/metabolism
MH  - Mitochondria/metabolism/pathology
MH  - Mitochondrial Diseases/*genetics/metabolism/pathology
MH  - Mutation
MH  - RNA Folding
MH  - RNA Precursors/*chemistry/genetics/metabolism
MH  - *RNA Processing, Post-Transcriptional
MH  - RNA, Mitochondrial/*chemistry/genetics/metabolism
MH  - RNA, Transfer/*chemistry/genetics/metabolism
PMC - PMC7962481
OTO - NOTNLM
OT  - PRORP
OT  - RNase P
OT  - mitochondrial diseases
OT  - pre-tRNA
OT  - tRNA mutations
OT  - tRNA processing
EDAT- 2021/01/01 06:00
MHDA- 2021/04/22 06:00
PMCR- 2022/04/01
CRDT- 2020/12/31 05:19
PHST- 2020/07/07 00:00 [received]
PHST- 2020/12/16 00:00 [accepted]
PHST- 2021/01/01 06:00 [pubmed]
PHST- 2021/04/22 06:00 [medline]
PHST- 2020/12/31 05:19 [entrez]
PHST- 2022/04/01 00:00 [pmc-release]
AID - rna.077198.120 [pii]
AID - RA [pii]
AID - 10.1261/rna.077198.120 [doi]
PST - ppublish
SO  - RNA. 2021 Apr;27(4):420-432. doi: 10.1261/rna.077198.120. Epub 2020 Dec 30.