Human mitochondrial RNA polymerase: Structure–function, mechanism and inhibition
Transcription of the human mitochondrial genome is required for the expression of 13 subunits of the respiratory chain complexes involved in oxidative phosphorylation, which is responsible for meeting the cells' energy demands in the form of ATP. Also transcribed are the two rRNAs and 22 tRNAs...
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| Veröffentlicht in: | Biochimica et biophysica acta 2012-09, Vol.1819 (9-10), p.948-960 |
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| creator | Arnold, Jamie J. Smidansky, Eric D. Moustafa, Ibrahim M. Cameron, Craig E. |
| description | Transcription of the human mitochondrial genome is required for the expression of 13 subunits of the respiratory chain complexes involved in oxidative phosphorylation, which is responsible for meeting the cells' energy demands in the form of ATP. Also transcribed are the two rRNAs and 22 tRNAs required for mitochondrial translation. This process is accomplished, with the help of several accessory proteins, by the human mitochondrial RNA polymerase (POLRMT, also known as h-mtRNAP), a nuclear-encoded single-subunit DNA-dependent RNA polymerase (DdRp or RNAP) that is distantly related to the bacteriophage T7 class of single-subunit RNAPs. In addition to its role in transcription, POLRMT serves as the primase for mitochondrial DNA replication. Therefore, this enzyme is of fundamental importance for both expression and replication of the human mitochondrial genome. Over the past several years rapid progress has occurred in understanding POLRMT and elucidating the molecular mechanisms of mitochondrial transcription. Important accomplishments include development of recombinant systems that reconstitute human mitochondrial transcription in vitro, determination of the X-ray crystal structure of POLRMT, identification of distinct mechanisms for promoter recognition and transcription initiation, elucidation of the kinetic mechanism for POLRMT-catalyzed nucleotide incorporation and discovery of unique mechanisms of mitochondrial transcription inhibition including the realization that POLRMT is an off target for antiviral ribonucleoside analogs. This review summarizes the current understanding of POLRMT structure–function, mechanism and inhibition. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.
► The human mitochondrial RNA polymerase (POLRMT) transcribes the mitochondrial genome with the help of accessory factors. ► POLRMT is evolutionarily related to bacteriophage T7 RNAP. ► Understanding properties of POLRMT is central to comprehending the mechanism of human mitochondrial transcription. |
| doi_str_mv | 10.1016/j.bbagrm.2012.04.002 |
| format | Article |
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► The human mitochondrial RNA polymerase (POLRMT) transcribes the mitochondrial genome with the help of accessory factors. ► POLRMT is evolutionarily related to bacteriophage T7 RNAP. ► Understanding properties of POLRMT is central to comprehending the mechanism of human mitochondrial transcription.</description><subject>ATP</subject><subject>Crystal structure</subject><subject>DNA, Mitochondrial - genetics</subject><subject>DNA, Mitochondrial - metabolism</subject><subject>DNA-directed RNA polymerase</subject><subject>DNA-Directed RNA Polymerases - genetics</subject><subject>DNA-Directed RNA Polymerases - metabolism</subject><subject>Electron transport</subject><subject>Enzymes</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Genomes</subject><subject>Humans</subject><subject>Ionizing radiation</subject><subject>Kinetics</subject><subject>Mitochondria</subject><subject>Mitochondria - genetics</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial DNA</subject><subject>Mitochondrial RNA polymerase</subject><subject>Mitochondrion</subject><subject>Molecular modelling</subject><subject>mtRNAP</subject><subject>Nucleotides</subject><subject>Oxidative phosphorylation</subject><subject>Phages</subject><subject>POLRMT</subject><subject>primase</subject><subject>Promoters</subject><subject>Protein Biosynthesis</subject><subject>Protein Conformation</subject><subject>Replication</subject><subject>RNA, Ribosomal - chemistry</subject><subject>RNA, Ribosomal - genetics</subject><subject>rRNA</subject><subject>Structure-Activity Relationship</subject><subject>Structure-function relationships</subject><subject>Transcription</subject><subject>Transcription initiation</subject><subject>Transcription, Genetic</subject><subject>Translation</subject><subject>tRNA</subject><issn>1874-9399</issn><issn>0006-3002</issn><issn>1876-4320</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkMFu1DAQhi0EoqXwBgjlyIGEGdvrOByQqgooUgVSgbPl2LOsV7Gz2Eml3voOfUOehCzb9og4zWjmm_mlj7GXCA0Cqrfbpu_tzxwbDsgbkA0Af8SOUbeqloLD47-9rDvRdUfsWSlbAIUc4Ck74ny1wlbLY3Z5Pkebqhim0W3G5HOwQ3X55bTajcN1pGwLvau-TXl205zp983tek5uCmN6U0VyG5tCiZVNvgppE_qw3zxnT9Z2KPTirp6wHx8_fD87ry--fvp8dnpRO6lwqhX5lnrRrhXIXmmNQnjSCNZ3uhWyU7z3xPkyQCcsoJacS0L0negJrRMn7PXh7y6Pv2Yqk4mhOBoGm2ici0EQWqHClf4fFMQKQe1ReUBdHkvJtDa7HKLN1wtk9uLN1hzEm714A9Is4pezV3cJcx_JPxzdm16A9weAFiVXgbIpLlBy5EMmNxk_hn8n_AHRuJYu</recordid><startdate>201209</startdate><enddate>201209</enddate><creator>Arnold, Jamie J.</creator><creator>Smidansky, Eric D.</creator><creator>Moustafa, Ibrahim M.</creator><creator>Cameron, Craig E.</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>201209</creationdate><title>Human mitochondrial RNA polymerase: Structure–function, mechanism and inhibition</title><author>Arnold, Jamie J. ; Smidansky, Eric D. ; Moustafa, Ibrahim M. ; Cameron, Craig E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c461t-6ed7eb37f604b688133de810ad98734962bde2210a1c3a0184224e11d93be1ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>ATP</topic><topic>Crystal structure</topic><topic>DNA, Mitochondrial - genetics</topic><topic>DNA, Mitochondrial - metabolism</topic><topic>DNA-directed RNA polymerase</topic><topic>DNA-Directed RNA Polymerases - genetics</topic><topic>DNA-Directed RNA Polymerases - metabolism</topic><topic>Electron transport</topic><topic>Enzymes</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Genomes</topic><topic>Humans</topic><topic>Ionizing radiation</topic><topic>Kinetics</topic><topic>Mitochondria</topic><topic>Mitochondria - genetics</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondrial DNA</topic><topic>Mitochondrial RNA polymerase</topic><topic>Mitochondrion</topic><topic>Molecular modelling</topic><topic>mtRNAP</topic><topic>Nucleotides</topic><topic>Oxidative phosphorylation</topic><topic>Phages</topic><topic>POLRMT</topic><topic>primase</topic><topic>Promoters</topic><topic>Protein Biosynthesis</topic><topic>Protein Conformation</topic><topic>Replication</topic><topic>RNA, Ribosomal - chemistry</topic><topic>RNA, Ribosomal - genetics</topic><topic>rRNA</topic><topic>Structure-Activity Relationship</topic><topic>Structure-function relationships</topic><topic>Transcription</topic><topic>Transcription initiation</topic><topic>Transcription, Genetic</topic><topic>Translation</topic><topic>tRNA</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Arnold, Jamie J.</creatorcontrib><creatorcontrib>Smidansky, Eric D.</creatorcontrib><creatorcontrib>Moustafa, Ibrahim M.</creatorcontrib><creatorcontrib>Cameron, Craig E.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Biochimica et biophysica acta</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Arnold, Jamie J.</au><au>Smidansky, Eric D.</au><au>Moustafa, Ibrahim M.</au><au>Cameron, Craig E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human mitochondrial RNA polymerase: Structure–function, mechanism and inhibition</atitle><jtitle>Biochimica et biophysica acta</jtitle><addtitle>Biochim Biophys Acta</addtitle><date>2012-09</date><risdate>2012</risdate><volume>1819</volume><issue>9-10</issue><spage>948</spage><epage>960</epage><pages>948-960</pages><issn>1874-9399</issn><issn>0006-3002</issn><eissn>1876-4320</eissn><abstract>Transcription of the human mitochondrial genome is required for the expression of 13 subunits of the respiratory chain complexes involved in oxidative phosphorylation, which is responsible for meeting the cells' energy demands in the form of ATP. Also transcribed are the two rRNAs and 22 tRNAs required for mitochondrial translation. This process is accomplished, with the help of several accessory proteins, by the human mitochondrial RNA polymerase (POLRMT, also known as h-mtRNAP), a nuclear-encoded single-subunit DNA-dependent RNA polymerase (DdRp or RNAP) that is distantly related to the bacteriophage T7 class of single-subunit RNAPs. In addition to its role in transcription, POLRMT serves as the primase for mitochondrial DNA replication. Therefore, this enzyme is of fundamental importance for both expression and replication of the human mitochondrial genome. Over the past several years rapid progress has occurred in understanding POLRMT and elucidating the molecular mechanisms of mitochondrial transcription. Important accomplishments include development of recombinant systems that reconstitute human mitochondrial transcription in vitro, determination of the X-ray crystal structure of POLRMT, identification of distinct mechanisms for promoter recognition and transcription initiation, elucidation of the kinetic mechanism for POLRMT-catalyzed nucleotide incorporation and discovery of unique mechanisms of mitochondrial transcription inhibition including the realization that POLRMT is an off target for antiviral ribonucleoside analogs. This review summarizes the current understanding of POLRMT structure–function, mechanism and inhibition. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.
► The human mitochondrial RNA polymerase (POLRMT) transcribes the mitochondrial genome with the help of accessory factors. ► POLRMT is evolutionarily related to bacteriophage T7 RNAP. ► Understanding properties of POLRMT is central to comprehending the mechanism of human mitochondrial transcription.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>22551784</pmid><doi>10.1016/j.bbagrm.2012.04.002</doi><tpages>13</tpages></addata></record> |
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| subjects | ATP Crystal structure DNA, Mitochondrial - genetics DNA, Mitochondrial - metabolism DNA-directed RNA polymerase DNA-Directed RNA Polymerases - genetics DNA-Directed RNA Polymerases - metabolism Electron transport Enzymes Gene expression Gene Expression Regulation Genomes Humans Ionizing radiation Kinetics Mitochondria Mitochondria - genetics Mitochondria - metabolism Mitochondrial DNA Mitochondrial RNA polymerase Mitochondrion Molecular modelling mtRNAP Nucleotides Oxidative phosphorylation Phages POLRMT primase Promoters Protein Biosynthesis Protein Conformation Replication RNA, Ribosomal - chemistry RNA, Ribosomal - genetics rRNA Structure-Activity Relationship Structure-function relationships Transcription Transcription initiation Transcription, Genetic Translation tRNA |
| title | Human mitochondrial RNA polymerase: Structure–function, mechanism and inhibition |
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