Abstract
Expansion of (CTG)n•(CAG)n trinucleotide repeat (TNR) microsatellite sequences is the cause of more than a dozen human neurodegenerative diseases. (CTG)n and (CAG)n repeats form imperfectly base paired hairpins that tend to expand in vivo in a length-dependent manner. Yeast, mouse and human models confirm that (CTG)n•(CAG)n instability increases with repeat number, and implicate both DNA replication and DNA damage response mechanisms in (CTG)n•(CAG)n TNR expansion and contraction. Mutation and knockdown models that abrogate the expression of individual genes might also mask more subtle, cumulative effects of multiple additional pathways on (CTG)n•(CAG)n instability in whole animals. The identification of second site genetic modifiers may help to explain the variability of (CTG)n•(CAG)n TNR instability patterns between tissues and individuals, and offer opportunities for prognosis and treatment.
Highlights
Expansion of (CTG)n(CAG)n trinucleotide repeat (TNR) sequences at distinct chromosomal loci is the mutation common to multiple neurological diseases including myotonic dystrophy type 1 (DM1), Huntington disease (HD), Huntington disease-like 2 (HDL2), dentatorubral-pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and several forms of spinocerebellar ataxia (SCA)
(CTG)n(CAG)n expansion at the DMPK 3’ UTR alters the chromatin structure of the region, downregulates transcription of the locus and, as at the JPH3 gene produce poly-(CUG) pre-mRNAs respectively in DM1 and HDL2 patients that sequester the MBNL (CUG) binding proteins, leading to trans-dominant interference with the normal splicing of multiple RNAs
Hairpins have been postulated to arise during replication fork reversal and postreplication repair [2,15,16], Okazaki fragment maturation [17,18,19], base excision repair [20], nucleotide excision repair [21,22,23,24,25,26] or repair of structures induced by R-loop formation during transcription [25,27]
Summary
Expansion of (CTG)n(CAG)n trinucleotide repeat (TNR) sequences at distinct chromosomal loci is the mutation common to multiple neurological diseases including myotonic dystrophy type 1 (DM1), Huntington disease (HD), Huntington disease-like 2 (HDL2), dentatorubral-pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and several forms of spinocerebellar ataxia (SCA). A ctf deletion mutant is associated with chromosomal instability, ctf rad double mutants grow poorly and produce a high percentage of inviable cells [100], and ctf mrc mutants are inviable [101] Taken together these studies in yeast suggest a cellular fail-safe strategy of overlapping pathways to (i) prevent the formation of stable hairpin structures by maintaining the rate of replisome movement and coupling of leading and lagging strand polymerases to the replicative helicase, (ii) restore hairpin structures to duplex DNA by repair helicases, and (iii) recruit postreplication repair machinery to excise hairpins.
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