An appraisal of human mitochondrial DNA instability: new insights into the role of non-canonical DNA structures and sequence motifs

PLoS One. 2013;8(3):e59907. doi: 10.1371/journal.pone.0059907. Epub 2013 Mar 29.

Abstract

Mitochondrial DNA (mtDNA) deletion mutations are frequently observed in aged postmitotic tissues and are the cause of a wide range of human disorders. Presently, the molecular bases underlying mtDNA deletion formation remain a matter of intense debate, and it is commonly accepted that several mechanisms contribute to the spectra of mutations in the mitochondrial genome. In this work we performed an extensive screening of human mtDNA deletions and evaluated the association between breakpoint density and presence of non-canonical DNA elements and over-represented sequence motifs. Our observations support the involvement of helix-distorting intrinsically curved regions and long G-tetrads in eliciting instability events. In addition, higher breakpoint densities were consistently observed within GC-skewed regions and in the close vicinity of the degenerate sequence motif YMMYMNNMMHM. A parallelism is also established with hot spot motifs previously identified in the nuclear genome, as well as with the minimal binding site for the mitochondrial transcription termination factor mTERF. This study extends the current knowledge on the mechanisms driving mitochondrial rearrangements and opens up exciting avenues for further research.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Binding Sites
  • DNA, Mitochondrial / chemistry
  • DNA, Mitochondrial / genetics*
  • Gene Deletion*
  • Genome, Mitochondrial*
  • Genomic Instability*
  • Humans
  • Mitochondrial Proteins / genetics
  • Nucleic Acid Conformation
  • Sequence Deletion

Substances

  • Basic-Leucine Zipper Transcription Factors
  • DNA, Mitochondrial
  • MTERF1 protein, human
  • Mitochondrial Proteins

Grants and funding

This work was supported by Fundação para a Ciência e a Tecnologia (FCT) through the MIT-Portugal Program, Bioengineering Focus Area and Project PTDC/EQU-EQU/114231/2009. PHO acknowledges FCT for the Post-Doctoral Grant BPD/64652/2009. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.