Triplet repeat DNA structures and human genetic disease: dynamic mutations from dynamic DNA

Abstract

Fourteen genetic neurodegenerative diseases and three fragile sites have been associated with the expansion of (CTG)n (CAG)n, (CGG)n (CCG)n, or (GAA)n (TTC)n repeat tracts. Different models have been proposed for the expansion of triplet repeats, most of which presume the formation of alternative DNA structures in repeat tracts. One of the most likely structures, slipped strand DNA, may stably and reproducibly form within triplet repeat sequences. The propensity to form slipped strand DNA is proportional to the length and homogeneity of the repeat tract. The remarkable stability of slipped strand DNA may, in part, be due to loop-loop interactions facilitated by the sequence complementarity of the loops and the dynamic structure of three-way junctions formed at the loop-outs.

The (CAG)n tract of Machado–Joseph Disease gene (ATXN3): a comparison between DNA and mRNA in patients and controls

“…It is known that triplet repeat sequences are able to form alternative structures, such as slipped strand structures. 15 The presence of those structures along the gDNA template may cause transient pausing and backward slippage of the RNA polymerase complex. As it was proposed previously, from the study of yeast models with long CAG or CTG tracts, 11 this could result in the resynthesis of the same RNA sequence, leading to the formation of longer transcripts.…”

Interactions of mutant p53 with DNA: guilt by association

“…Interestingly, the ability of mutp53 proteins to bind non-canonic DNA structures formed by (CTG CAG) tracts is not unique to mutp53, but derives from the inherent DNA structure-dependent binding (DSDB) activity of wtp53 (Go¨hler et al, 2002;Walter et al, 2005). Considering that out the formation of hairpin and slipped DNA structures is the underlying mechanism of (CTG CAG) tract instability associated with several neurodegenerative diseases (Sinden et al, 2002), the finding that wtp53 and mutp53 proteins target (CTG CAG) tracts in a DSSB mode may provide important insights into the emerging connection between wtp53 and neurodegenerative diseases (Bae et al, 2005;Feng et al, 2006). Whereas an involvement of mutp53 in the pathophysiology of neurodegenerative diseases seems to be rather unlikely, a more intriguing possibility is that the binding of (CTG CAG) tracts by mutp53 proteins could be relevant for establishing specific patterns of chromatin structure in cancer cells.…”

Hairpin Structure-forming Propensity of the (CCTG·CAGG) Tetranucleotide Repeats Contributes to the Genetic Instability Associated with Myotonic Dystrophy Type 2

“…it contains no polymorphisms/interruptions) as determined by sequencing of the entire repeat containing tract. The (CCTG⅐CAGG) 114 and the (CCTG⅐CAGG) 200 carried a single base pair interruption 11 repeats into the tract to give the sequence (CCTG) 11 CCTT(CCTG) n , where n ϭ 102 and 188, respectively. The (CCTG⅐CAGG) n (where n ϭ 114 or 200) repeats were sequenced using primers located at both ends of the repeating tract.…”

“…myotonic dystrophy, fragile X syndrome, and Friedreich's ataxia) are associated with the expansions of (CTG⅐CAG) n , (CGG⅐CCG) n , or (GAA⅐TTC) n repeat tracts, respectively (7)(8)(9)(10)(11)(12)(13). Additionally, two other non-triplet repeat neurological diseases, spinocerebellar ataxia type 10 (SCA10) (14) and progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) (15), are caused by the expansions of pentanucleotide and dodecanucleotide repeating sequences, respectively.…”