On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Abstract

Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

Huntingtin lowering reduces somatic instability at CAG-expanded loci

“…They reduce instability in at least one other repeat expanded locus ( Atxn2 ), suggesting they are worth considering as treatments in other repeat expansion diseases -a large family of currently untreatable conditions 26 . Many disease-associated repeats exhibit somatic expansion 27 that is thought to play a role in driving the rate of pathogenesis 28 . Therefore, to the extent that repeat expansion in relevant cell types in these disorders is sensitive to HTT levels, HTT-lowering treatments may prove effective in multiple indications.…”

Quantifying Structural Diversity of CNG Trinucleotide Repeats Using Diagrammatic Algorithms

“…The entropy of graph (2,2) is similar to (2,1). This is not surprising because their topologies are similar, except two segments in (2,2) are constrained into a 2-way junction, whereas in (2,1) one of them is constrained inside a hairpin and the other is free. Contrasting this to the graph (2,3) in Fig.…”

“…Going from (3,4) to (4,14), the entropy value of the necklace diagram actually increases from Δ / = 8.51 to 9.38, growing from ~5000 to 12000 configurations. Furthermore, some of the other partial necklace diagrams, such as (3,2) in Fig. 9 and (4,4) and (4,8), also increase in diversity going from low to higher order.…”

A Timeless Tale: G4 structure recognition by the fork protection complex triggers unwinding by DDX 11 helicase

“…These findings have important implications for how genomes replicate through the numerous structure‐forming DNA sequences in the human genome. One outcome of inappropriate replication of DNA structures is repeat expansion diseases (Khristich & Mirkin, ). Also, over‐expression of FPC members Claspin and Timeless has recently been identified as one of the strategies used by cancer cells to increase tolerance to oncogene‐induced replication stress (Bianco et al , ).…”