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Human mitochondrial RNA polymerase: structure-function, mechanism and inhibition.
Jamie J Arnold1, Eric D Smidansky, Ibrahim M Moustafa
1Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA. jja5@psu.edu
Biochimica Et Biophysica Acta
|May 4, 2012
Summary
Human mitochondrial RNA polymerase (POLRMT) is crucial for mitochondrial gene expression and DNA replication. Recent advances clarify its structure, function, and inhibition mechanisms, including its role in antiviral drug action.
Area of Science:
- Molecular Biology
- Biochemistry
- Genetics
Background:
- Mitochondrial transcription is essential for cellular energy production via oxidative phosphorylation.
- Human mitochondrial RNA polymerase (POLRMT) transcribes mitochondrial genes and acts as a primase for DNA replication.
- POLRMT is a nuclear-encoded, single-subunit RNA polymerase distantly related to bacteriophage T7 RNAPs.
Purpose of the Study:
- To review the current understanding of POLRMT structure-function.
- To elucidate the molecular mechanisms of mitochondrial transcription and replication.
- To summarize POLRMT inhibition mechanisms and its role with antiviral agents.
Main Methods:
- In vitro reconstitution of human mitochondrial transcription.
- X-ray crystallography of POLRMT.
- Kinetic analysis of nucleotide incorporation.
Main Results:
- Distinct mechanisms for POLRMT promoter recognition and transcription initiation identified.
- Elucidation of the kinetic mechanism for POLRMT-catalyzed nucleotide incorporation.
- POLRMT identified as an off-target for antiviral ribonucleoside analogs.
Conclusions:
- POLRMT is a fundamental enzyme for human mitochondrial genome expression and replication.
- Significant progress has been made in understanding POLRMT's structure, function, and regulation.
- POLRMT's unique inhibition mechanisms offer insights into potential therapeutic strategies.
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