Structural Basis of Mitochondrial Transcription Initiation

Cell. 2017 Nov 16;171(5):1072-1081.e10. doi: 10.1016/j.cell.2017.10.036.

Abstract

Transcription in human mitochondria is driven by a single-subunit, factor-dependent RNA polymerase (mtRNAP). Despite its critical role in both expression and replication of the mitochondrial genome, transcription initiation by mtRNAP remains poorly understood. Here, we report crystal structures of human mitochondrial transcription initiation complexes assembled on both light and heavy strand promoters. The structures reveal how transcription factors TFAM and TFB2M assist mtRNAP to achieve promoter-dependent initiation. TFAM tethers the N-terminal region of mtRNAP to recruit the polymerase to the promoter whereas TFB2M induces structural changes in mtRNAP to enable promoter opening and trapping of the DNA non-template strand. Structural comparisons demonstrate that the initiation mechanism in mitochondria is distinct from that in the well-studied nuclear, bacterial, or bacteriophage transcription systems but that similarities are found on the topological and conceptual level. These results provide a framework for studying the regulation of gene expression and DNA replication in mitochondria.

Keywords: Initiation; Initiation Complex; Mitochondria; POLRMT; Polymerase; TEFM; TFAM; TFB2M; Transcription.

MeSH terms

  • Amino Acid Sequence
  • Bacteriophage T7 / enzymology
  • Bacteriophage T7 / metabolism
  • DNA, Mitochondrial / chemistry
  • DNA, Mitochondrial / metabolism*
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / isolation & purification
  • DNA-Binding Proteins / metabolism
  • DNA-Directed RNA Polymerases / metabolism
  • Gene Expression Regulation
  • Humans
  • Methyltransferases / chemistry*
  • Methyltransferases / isolation & purification
  • Methyltransferases / metabolism
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / chemistry*
  • Mitochondrial Proteins / isolation & purification
  • Mitochondrial Proteins / metabolism
  • Models, Molecular
  • Multiprotein Complexes / chemistry
  • Promoter Regions, Genetic
  • Sequence Alignment
  • Transcription Factors / chemistry*
  • Transcription Factors / isolation & purification
  • Transcription Factors / metabolism
  • Transcription Initiation, Genetic*
  • Transcription, Genetic

Substances

  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • Multiprotein Complexes
  • TFAM protein, human
  • Transcription Factors
  • Methyltransferases
  • TFB2M protein, human
  • DNA-Directed RNA Polymerases