The contribution of <i>cis</i>-elements to disease-associated repeat instability: clinical and experimental evidence

Abstract

Alterations in the length (instability) of gene-specific microsatellites and minisatellites are associated with at least 35 human diseases. This review will discuss the various cis-elements that contribute to repeat instability, primarily through examination of the most abundant disease-associated repetitive element, trinucleotide repeats. For the purpose of this review, we define cis-elements to include the sequence of the repeat units, the length and purity of the repeat tracts, the sequences flanking the repeat, as well as the surrounding epigenetic environment, including DNA methylation and chromatin structure. Gender-, tissue-, developmental- and locus-specific cis-elements in conjunction with trans-factors may facilitate instability through the processes of DNA replication, repair and/or recombination. Here we review the available human data that supports the involvement of cis-elements in repeat instability with limited reference to model systems. In diverse tissues at different developmental times and at specific loci, repetitive elements display variable levels of instability, suggesting vastly different mechanisms may be responsible for repeat instability amongst the disease loci and between various tissues.

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles

“…Furthermore, the comparison disclosed highly significant differences and strong effect of the CAG length in the somatic mosaicism, assessed either as mosaicism index (MI) or as peak numbers (F(1,243)¼131.57, P¼0.00, ANOVA followed by Bonferroni post hoc test, 20-26 vs 27-31 CAG range, MI ± SEM: 0.00 ± 0.016, 0.385 ± 0.028, respectively, P¼0.000) (Supplementary Figures S3a and b). According to our current results with regard to the differences between somatic mosaicism and the known phenotypic range of SCA2, we extended the previous comparison to a cohort of 551 alleles with the following ranges: normal (20)(21)(22)(23)(24)(25)(26), large (27)(28)(29)(30)(31), intermediate (32)(33)(34) and expanded . In addition to the differences in normal CAG repeat ranges, the levels of somatic mosaicism of 32-34 CAG alleles were lower than those observed in the full penetrant expanded alleles (35-79 CAG) (MI±SEM: 0.632±0.11 and 2.51±0.25, respectively, P¼0.000) (Figures 3a-c).…”

“…Previously, it has been stated that longer alleles in the normal range present a higher probability of pathogenic expansion than do shorter alleles. 32,33 Therefore, this makes more likely the contribution of the former group to the onset of de novo mutations. In this state, IAs with 32-35 CAG repeats that may have evolved from large ANs with 23-31 CAG repeats are intermediates, which in successive generations would give rise to full penetrant alleles (37-79 CAG) associated with SCA2, ALS, 34 FTDP-U, 34 or pure parkinsonism.…”

Concerted Action of Exonuclease and Gap-dependent Endonuclease Activities of FEN-1 Contributes to the Resolution of Triplet Repeat Sequences (CTG) - and (GAA) -derived Secondary Structures Formed during Maturation of Okazaki Fragments

“…6B). When wild type protein was used, the FEN cleavage products (17,16, and 15 nt) can be observed, followed by EXO cleavage products (10 -14 nt), which increase in intensity as the reaction progresses. When E176A is used, only FEN cleavage products are observed, along with a low fraction of EXO cleavage products.…”

“…In vivo studies of TNR stability have taken advantage of model systems in Escherichia coli, yeast, mice, and cell lines. Processes implicated in repeat tract instability include replication slippage, the direction of replication fork progression, lagging strand errors, Okazaki fragment processing, mismatch repair, gap filling, double strand break repair, and recombination (17). These mechanisms are not mutually exclusive, and any combination of them may result in significant TNR expansion and a disease phenotype in higher organisms.…”

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

“…Each of these processes exposes single strands of repeats, which can form secondary structures such as hairpins and slipped-strand duplexes (10,41), which are thought to be the key intermediates that trigger repeat instability. As if that were not enough diversity, additional identified contributors to instability include epigenetic modifications, chromatin structure, and local sequence effects (4,7). Thus, the molecular details of repeat instability, especially the number of relevant pathways and the interconnections among them, are not yet clear.…”