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.
Highlights
Repetitive DNA sequence elements are widely abundant in the human and the other eukaryotic genomes
The trinucleotide repeats sequences (TRS) represent the most common type of tandem microsatellites in the vertebrate genomic DNA. Such genomic elements were found in the coding and the noncoding DNA co-localizing with human chromosomal fragile sites that are associated with genomic breakpoints in cancer and a growing number of devastating human diseases [1,2,3,4,5]
We report a novel coherent DNA breathing behavior in TRSs that is readily calculated using the EPBD derived values of the base pairs average displacements
Summary
Repetitive DNA sequence elements are widely abundant in the human and the other eukaryotic genomes. They are classified into two large families, the ‘‘tandem’’ and ‘‘dispersed’’ repeats. The trinucleotide repeats sequences (TRS) represent the most common type of tandem microsatellites in the vertebrate genomic DNA. Such genomic elements were found in the coding and the noncoding DNA co-localizing with human chromosomal fragile sites that are associated with genomic breakpoints in cancer and a growing number of devastating human diseases [1,2,3,4,5]. In the fragile X syndrome (FXS) the (CGG.GCC) expansion in the 59 untranslated region of the FMR1 gene causes the transcriptional silencing of the gene [12]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have