title: DNA dynamics is likely to be a factor in the genomic nucleotide repeats expansions related to diseases.
abstract: 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.
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Boian S
authors.initials: BS
authors.lastname: Alexandrov
authors.forename: Vlad I
authors.initials: VI
authors.lastname: Valtchinov
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gelev
authors.forename: Yossi
authors.initials: Y
authors.lastname: Dagon
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bock
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Kohane
authors.forename: Kim Ø
authors.initials: KØ
authors.lastname: Rasmussen
authors.forename: Alan R
authors.initials: AR
authors.lastname: Bishop
authors.forename: Anny
authors.initials: A
authors.lastname: Usheva
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006367:HeLa Cells; D006801:Humans; D008390:Markov Chains; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D014157:Transcription Factors; D004247:DNA