Trinucleotide repeat instability: a hairpin curve at the crossroads of replication, recombination, and repair

Lenzmeier, Brian A.; Freudenreich, Catherine H.

doi:10.1159/000072836

Cited by 86 publications

(90 citation statements)

References 197 publications

(297 reference statements)

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“…Supercoiling has been shown to play a role in the instability of CGG, GAA, and CAG repeats in bacteria (38), but not previously in mammalian cells. In bacteria the link has been ascribed to the effects of negative supercoiling on enhancing the formation of repeat-induced non-B DNA structures (38), which are thought to constitute the key common event leading to changes in repeat-tract length (24,40,56). The negative supercoiling that develops behind a transcribing RNA polymerase (54) would provide a natural connection between transcription and repeat instability and could explain our results with TOP1 inhibitors, especially with siRNA knockdowns of TOP1, which might be expected to increase supercoiling stress (9).…”

Section: Discussionmentioning

confidence: 99%

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

Hubert

Lin

Dion

et al. 2011

Molecular and Cellular Biology

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Expanded trinucleotide repeats are responsible for a number of neurodegenerative diseases, such as Huntington disease and myotonic dystrophy type 1. The mechanisms that underlie repeat instability in the germ line and in the somatic tissues of human patients are undefined. Using a selection assay based on contraction of CAG repeat tracts in human cells, we screened the Prestwick chemical library in a moderately highthroughput assay and identified 18 novel inducers of repeat contraction. A subset of these compounds targeted pathways involved in the management of DNA supercoiling associated with transcription. Further analyses using both small molecule inhibitors and small interfering RNA (siRNA)-mediated knockdowns demonstrated the involvement of topoisomerase 1 (TOP1), tyrosyl-DNA phosphodiesterase 1 (TDP1), and single-strand break repair (SSBR) in modulating transcription-dependent CAG repeat contractions. The TOP1-TDP1-SSBR pathway normally functions to suppress repeat instability, since interfering with it stimulated repeat contractions. We further showed that the increase in repeat contractions when the TOP1-TDP1-SSBR pathway is compromised arises via transcription-coupled nucleotide excision repair, a previously identified contributor to transcription-induced repeat instability. These studies broaden the scope of pathways involved in transcription-induced CAG repeat instability and begin to define their interrelationships.

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Section: Discussionmentioning

confidence: 99%

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

Hubert

Lin

Dion

et al. 2011

Molecular and Cellular Biology

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“…The (CTG) n · (CAG) n TNR can cause DNA polymerase stuttering and form hairpin structures in vitro (4)(5)(6)(7) and in vivo (8), which lead to TNR length instability (contraction or expansion). TNR hairpins may be formed during DNA replication (8), transcription (9), and DNA repair (10). Particularly in postmitotic cells, mismatch repair (MMR) pathways are thought to play a role in TNR instability, although the precise role of human MMR in (CTG) n · (CAG) n stability in humans remains unresolved (11,12).…”

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confidence: 99%

Oligodeoxynucleotide Binding to (CTG) · (CAG) Microsatellite Repeats Inhibits Replication Fork Stalling, Hairpin Formation, and Genome Instability

Liu

Chen

Leffak

2013

Molecular and Cellular Biology

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(CTG) n · (CAG) n trinucleotide repeat (TNR) expansion in the 3= untranslated region of the dystrophia myotonica protein kinase (DMPK) gene causes myotonic dystrophy type 1. However, a direct link between TNR instability, the formation of noncanonical (CTG) n · (CAG) n structures, and replication stress has not been demonstrated. In a human cell model, we found that (CTG) 45 · (CAG) 45 causes local replication fork stalling, DNA hairpin formation, and TNR instability. Oligodeoxynucleotides (ODNs) complementary to the (CTG) 45 · (CAG) 45 lagging-strand template eliminated DNA hairpin formation on leading-and laggingstrand templates and relieved fork stalling. Prolonged cell culture, emetine inhibition of lagging-strand synthesis, or slowing of DNA synthesis by low-dose aphidicolin induced (CTG) 45 · (CAG) 45 expansions and contractions. ODNs targeting the laggingstrand template blocked the time-dependent or emetine-induced instability but did not eliminate aphidicolin-induced instability. These results show directly that TNR replication stalling, replication stress, hairpin formation, and instability are mechanistically linked in vivo.

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“…However, the DNA sequence and structure itself also determines the fidelity of genome propagation, with each class of repeat DNA (i.e., ribosomal DNA, telomeres, trinucleotide repeats, and transposons) presenting unique challenges to the genome. There are pathways that predominate to ensure control of each repeat type [e.g., chromatin cohesion and transcriptional silencing are needed to stabilize ribosomal DNA repeat copy number whereas trinucleotide repeat array integrity depends on accurate DNA replication and mismatch repair (4,5)], but the precise interactions of repetitive DNA with the various DNA repair pathways remain unidentified.…”

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confidence: 99%

Retrotransposon overdose and genome integrity

Scheifele

Cost²,

Zupancic³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Yeast and mammalian genomes are replete with nearly identical copies of long dispersed repeats in the form of retrotransposons. Mechanisms clearly exist to maintain genome structure in the face of potential rearrangement between the dispersed repeats, but the nature of this machinery is poorly understood. Here we describe a series of distinct ''retrotransposon overdose'' (RO) lineages in which the number of Ty1 elements in the Saccharomyces cerevisiae genome has been increased by as much as 10 fold. Although these RO strains are remarkably normal in growth rate, they demonstrate an intrinsic supersensitivity to DNA-damaging agents. We describe the identification of mutants in the DNA replication pathway that enhance this RO-specific DNA damage supersensitivity by promoting ectopic recombination between Ty1 elements. Abrogation of normal DNA replication leads to rampant genome instability primarily in the form of chromosomal aberrations and confirms the central role of DNA replication accuracy in the stabilization of repetitive DNA.chromosome rearrangement ͉ genome instability ͉ Ty1 elements

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Trinucleotide repeat instability: a hairpin curve at the crossroads of replication, recombination, and repair

Cited by 86 publications

References 197 publications

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

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

Oligodeoxynucleotide Binding to (CTG) · (CAG) Microsatellite Repeats Inhibits Replication Fork Stalling, Hairpin Formation, and Genome Instability

Retrotransposon overdose and genome integrity

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