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An appraisal of human mitochondrial DNA instability: new insights into the role of non-canonical DNA structures and sequence motifs
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 mechan...
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| Published in: | PloS one 2013-03, Vol.8 (3), p.e59907 |
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| creator | Oliveira, Pedro H da Silva, Cláudia Lobato Cabral, Joaquim M S |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0059907 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0059907</identifier><identifier>PMID: 23555828</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino Acid Motifs ; Basic-Leucine Zipper Transcription Factors - genetics ; Binding Sites ; Bioengineering ; Biology ; Biotechnology ; Deoxyribonucleic acid ; DNA ; DNA, Mitochondrial - chemistry ; DNA, Mitochondrial - genetics ; Gene Deletion ; Genome, Mitochondrial ; Genomes ; Genomic Instability ; Humans ; Mitochondrial DNA ; Mitochondrial Proteins - genetics ; Mutation ; Nucleic Acid Conformation ; Nucleotide sequence ; Sequence Deletion ; Tetrads ; Tissues ; Transcription termination</subject><ispartof>PloS one, 2013-03, Vol.8 (3), p.e59907</ispartof><rights>2013 Oliveira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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. 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| subjects | Amino Acid Motifs Basic-Leucine Zipper Transcription Factors - genetics Binding Sites Bioengineering Biology Biotechnology Deoxyribonucleic acid DNA DNA, Mitochondrial - chemistry DNA, Mitochondrial - genetics Gene Deletion Genome, Mitochondrial Genomes Genomic Instability Humans Mitochondrial DNA Mitochondrial Proteins - genetics Mutation Nucleic Acid Conformation Nucleotide sequence Sequence Deletion Tetrads Tissues Transcription termination |
| title | An appraisal of human mitochondrial DNA instability: new insights into the role of non-canonical DNA structures and sequence motifs |
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