title: An appraisal of human mitochondrial DNA instability: new insights into the role of non-canonical DNA structures and sequence motifs.
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.
authors.affiliation: Department of Bioengineering and Institute for Biotechnology and Bioengineering, Instituto Superior Técnico, Lisbon, Portugal. pcphco@gmail.com
authors.forename: Pedro H
authors.initials: PH
authors.lastname: Oliveira
authors.forename: Cláudia Lobato
authors.initials: CL
authors.lastname: da Silva
authors.forename: Joaquim M S
authors.initials: JM
authors.lastname: Cabral
mesh_terms: D020816:Amino Acid Motifs; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D001665:Binding Sites; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics*; D017353:Gene Deletion; D054629:Genome, Mitochondrial; D042822:Genomic Instability; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics; D009690:Nucleic Acid Conformation; D017384:Sequence Deletion
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D004272:DNA, Mitochondrial; C105178:MTERF1 protein, human; D024101:Mitochondrial Proteins
references.citation: Mol Genet Metab. 2002 Jun;76(2):123-32
references.pmid: 12083809
references.citation: Mol Cell Biol. 1996 May;16(5):2119-27
references.pmid: 8628278
references.citation: RNA Biol. 2010 Sep-Oct;7(5):551-8
references.pmid: 20729633
references.citation: Mol Cell. 2012 Apr 27;46(2):115-24
references.pmid: 22541554
references.citation: Trends Genet. 2010 Aug;26(8):340-3
references.pmid: 20591530
references.citation: Nat Chem Biol. 2012 Feb 05;8(3):301-10
references.pmid: 22306580
references.citation: Cell Mol Life Sci. 2010 Jan;67(1):43-62
references.pmid: 19727556
references.citation: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W253-8
references.pmid: 17478497
references.citation: EMBO J. 1995 Apr 18;14(8):1812-8
references.pmid: 7737131
references.citation: Annu Rev Microbiol. 1997;51:593-628
references.pmid: 9343361
references.citation: J Biol Chem. 1998 Nov 13;273(46):30614-21
references.pmid: 9804833
references.citation: Gene. 2001 Aug 22;274(1-2):271-81
references.pmid: 11675020
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3686-7
references.pmid: 12824394
references.citation: Trends Genet. 2000 Jun;16(6):276-7
references.pmid: 10827456
references.citation: Chembiochem. 2010 Feb 15;11(3):331-4
references.pmid: 20014270
references.citation: Nat Genet. 2008 Mar;40(3):275-9
references.pmid: 18305478
references.citation: Nucleic Acids Res. 2012 Sep;40(16):7606-21
references.pmid: 22661583
references.citation: J Hum Genet. 2011 Oct;56(10):689-94
references.pmid: 21866113
references.citation: Nucleic Acids Res. 2004 Jun 04;32(10):3053-64
references.pmid: 15181170
references.citation: Biochem J. 1996 Sep 15;318 ( Pt 3):1065-70
references.pmid: 8836157
references.citation: Genet Mol Res. 2008 Jun 24;7(2):549-58
references.pmid: 18752180
references.citation: Proc Int Conf Intell Syst Mol Biol. 1994;2:28-36
references.pmid: 7584402
references.citation: Nucleic Acids Res. 1994 Dec 11;22(24):5497-503
references.pmid: 7816643
references.citation: EMBO J. 1992 Dec;11(13):5063-70
references.pmid: 1464328
references.citation: Trends Genet. 2004 May;20(5):226-9
references.pmid: 15109774
references.citation: Mol Biol Evol. 2001 Jun;18(6):1139-42
references.pmid: 11371603
references.citation: Genomics. 1994 Jul 15;22(2):327-35
references.pmid: 7806218
references.citation: Mutat Res. 2001 Mar;488(1):9-23
references.pmid: 11223402
references.citation: Genome Res. 2004 Jun;14(6):1188-90
references.pmid: 15173120
references.citation: Nucleic Acids Res. 2005 May 24;33(9):2908-16
references.pmid: 15914667
references.citation: Mol Biol (Mosk). 2002 May-Jun;36(3):418-23
references.pmid: 12068625
references.citation: Genome Biol Evol. 2011;3:614-26
references.pmid: 21697099
references.citation: Nat Genet. 2008 Sep;40(9):1124-9
references.pmid: 19165926
references.citation: PLoS One. 2012;7(4):e35271
references.pmid: 22529999
references.citation: Trends Genet. 2004 Sep;20(9):393-8
references.pmid: 15313545
references.citation: Mutat Res. 1998 Jul 17;403(1-2):75-84
references.pmid: 9726008
references.citation: Nucleic Acids Res. 2007;35(19):6458-74
references.pmid: 17884915
references.citation: Nat Biotechnol. 1998 Oct;16(10):939-45
references.pmid: 9788350
references.citation: Biochim Biophys Acta. 2010 Feb;1797(2):113-28
references.pmid: 19761752
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D383-91
references.pmid: 21097885
references.citation: PLoS One. 2009;4(2):e4399
references.pmid: 19198658