DNA Dynamics Is Likely to Be a Factor in the Genomic Nucleotide Repeats Expansions Related to Diseases

Trinucleotide repeats sequences (TRS) represent a common type of genomic DNA motif whose expansion is associated with a large number of human diseases. The driving molecular mechanisms of the TRS ongoing dynamic expansion across generations and within tissues and its influence on genomic DNA functions are not well understood. Here we report results for a novel and notable collective breathing behavior of genomic DNA of tandem TRS, leading to propensity for large local DNA transient openings at physiological temperature. Our Langevin molecular dynamics (LMD) and Markov Chain Monte Carlo (MCMC) simulations demonstrate that the patterns of openings of various TRSs depend specifically on their length. The collective propensity for DNA strand separation of repeated sequences serves as a precursor for outsized intermediate bubble states independently of the G/C-content. We report that repeats have the potential to interfere with the binding of transcription factors to their consensus sequence by altered DNA breathing dynamics in proximity of the binding sites. These observations might influence ongoing attempts to use LMD and MCMC simulations for TRS–related modeling of genomic DNA functionality in elucidating the common denominators of the dynamic TRS expansion mutation with potential therapeutic applications.

[1]  R. Ballotti,et al.  Enhanced Binding of Poly(ADP-ribose)polymerase-1 and Ku80/70 to the ITGA2 Promoter via an Extended Cytosine-Adenosine Repeat , 2010, PloS one.

[2]  Stéphane Schmucker,et al.  Understanding the molecular mechanisms of Friedreich's ataxia to develop therapeutic approaches. , 2010, Human molecular genetics.

[3]  Alan R. Bishop,et al.  DNA dynamics play a role as a basal transcription factor in the positioning and regulation of gene transcription initiation , 2009, Nucleic acids research.

[4]  David M. Wilson,et al.  Stoichiometry of Base Excision Repair Proteins Correlates with Increased Somatic CAG Instability in Striatum over Cerebellum in Huntington's Disease Transgenic Mice , 2009, PLoS genetics.

[5]  A R Bishop,et al.  Bubble nucleation and cooperativity in DNA melting. , 2004, Physical review letters.

[6]  Audrey E Hendricks,et al.  Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset. , 2009, Human molecular genetics.

[7]  R. Wells.  DNA triplexes and Friedreich ataxia , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  C. E. Pearson,et al.  Repeat instability: mechanisms of dynamic mutations , 2005, Nature Reviews Genetics.

[9]  James T Kadonaga,et al.  Rational design of a super core promoter that enhances gene expression , 2006, Nature Methods.

[10]  R. Wells,et al.  R loops stimulate genetic instability of CTG·CAG repeats , 2009, Proceedings of the National Academy of Sciences.

[11]  B. Dujon,et al.  Comparative Genomics and Molecular Dynamics of DNA Repeats in Eukaryotes , 2008, Microbiology and Molecular Biology Reviews.

[12]  R. Wells,et al.  The chemistry and biology of unusual DNA structures adopted by oligopurine · oligopyrimidine sequences , 1988, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  Ben A. Oostra,et al.  Absence of expression of the FMR-1 gene in fragile X syndrome , 1991, Cell.

[14]  L. Alexandrov,et al.  A nonlinear dynamic model of DNA with a sequence-dependent stacking term , 2009, Nucleic acids research.

[15]  S. Burley,et al.  Crystal structure of a TFIIB–TBP–TATA-element ternary complex , 1995, Nature.

[16]  Shin Kwak,et al.  FRIEDREICH'S ATAXIA , 1917, Nihon rinsho. Japanese journal of clinical medicine.

[17]  C. E. Pearson,et al.  Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells , 2002, Nature Genetics.

[18]  Bishop,et al.  Statistical mechanics of a nonlinear model for DNA denaturation. , 1989, Physical review letters.

[19]  C. E. Pearson,et al.  Repeat instability as the basis for human diseases and as a potential target for therapy , 2010, Nature Reviews Molecular Cell Biology.

[20]  V. Zakian,et al.  Expansion and length-dependent fragility of CTG repeats in yeast. , 1998, Science.

[21]  Yan Zeng,et al.  Bubble nucleation and cooperativity in DNA melting. , 2004, Journal of molecular biology.

[22]  Stéphane Schmucker,et al.  Understanding the Molecular Mechanisms of Friedreich′s Ataxia to Develop Therapeutic Approaches , 2010 .

[23]  E. Greene,et al.  Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia , 2007, Nucleic acids research.

[24]  Thomas Shenk,et al.  TATA-binding protein-independent initiation: YY1, TFIIB, and RNA polymerase II direct basal transcription on supercoiled template DNA , 1994, Cell.

[25]  Sang Wook Yoo,et al.  Toward a Detailed Description of the Thermally Induced Dynamics of the Core Promoter , 2009, PLoS Comput. Biol..

[26]  M. Pandolfo,et al.  The Friedreich ataxia GAA triplet repeat: premutation and normal alleles. , 1997, Human molecular genetics.

[27]  Tetsuo Ashizawa,et al.  Unpaired structures in SCA10 (ATTCT)n.(AGAAT)n repeats. , 2003, Journal of molecular biology.

[28]  R. Wells,et al.  Non-B DNA conformations, mutagenesis and disease. , 2007, Trends in biochemical sciences.

[29]  Paul M. Rindler,et al.  Role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells , 2010, Nucleic Acids Res..

[30]  Huda Y. Zoghbi,et al.  Diseases of Unstable Repeat Expansion: Mechanisms and Common Principles , 2005, Nature Reviews Genetics.

[31]  Arne Klungland,et al.  OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells , 2007, Nature.

[32]  B. Kerem,et al.  The molecular basis of common and rare fragile sites. , 2006, Cancer letters.

[33]  A. Monticelli,et al.  Somatic instability of the expanded GAA triplet-repeat sequence in Friedreich ataxia progresses throughout life. , 2007, Genomics.

[34]  R. Schmid.  Gilbert's syndrome--a legitimate genetic anomaly? , 1995, The New England journal of medicine.

[35]  F. Squitieri,et al.  New Huntington disease mutation arising from a paternal CAG34 allele showing somatic length variation in serially passaged lymphoblasts , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[36]  S. Warren,et al.  Trinucleotide repeat expansion and human disease. , 1995, Annual review of genetics.