Models for chromosomal replication‐independent non‐B DNA structure‐induced genetic instability

Wang, Guliang; Vásquez, Karen M.

doi:10.1002/mc.20508

Cited by 48 publications

(48 citation statements)

References 163 publications

(185 reference statements)

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“…The evidence indicates that DSBs are formed at the repeat, followed by strand invasion of the sister chromatid, and mutagenic synthesis by Polζ during HR repair (Saini et al ., 2013). This repeat-induced mutagenesis (RIM) has also been observed for H-DNA- and Z-DNA-forming sequences introduced into mammalian cells (Wang & Vasquez, 2004, 2009; Wang et al ., 2006). Thus, the cis -effects of structure-forming DNA extend even beyond the repeat itself, influencing genome mutation rates over a large region.…”

Section: The Role Of Dsb Repair In Preventing Repeat Fragility and Inmentioning

confidence: 70%

Repeat instability during DNA repair: Insights from model systems

Usdin

House

Freudenreich

2015

Critical Reviews in Biochemistry and Molecular Biology

167

218

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The expansion of repeated sequences is the cause of over 30 inherited genetic diseases, including Huntington disease, myotonic dystrophy (types 1 and 2), fragile X syndrome, many spinocerebellar ataxias, and some cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansions are dynamic, and disease inheritance and progression are influenced by the size and the rate of expansion. Thus, an understanding of the various cellular mechanisms that cooperate to control or promote repeat expansions is of interest to human health. In addition, the study of repeat expansion and contraction mechanisms has provided insight into how repair pathways operate in the context of structure-forming DNA, as well as insights into non-canonical roles for repair proteins. Here we review the mechanisms of repeat instability, with a special emphasis on the knowledge gained from the various model systems that have been developed to study this topic. We cover the repair pathways and proteins that operate to maintain genome stability, or in some cases cause instability, and the cross-talk and interactions between them.

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Section: The Role Of Dsb Repair In Preventing Repeat Fragility and Inmentioning

confidence: 70%

Repeat instability during DNA repair: Insights from model systems

Usdin

House

Freudenreich

2015

Critical Reviews in Biochemistry and Molecular Biology

167

218

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“…triplex, quadruplex, Z-DNA, cruciforms, slipped structures) at the breakpoint junctions of chromosomal alterations (gross deletions and duplications) associated with human genetic disease, including cystic fibrosis, mental retardation, and multiple congenital anomalies (1). These observations have served to extend the generality of previous work that aimed to elucidate the molecular mechanisms underlying recurrent translocations (2-6) and the genetic instability observed in many model systems (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), both of which were suggestive of a direct mutagenic role for non-B DNA. In the same vein, analyses of DNA sequence motifs flanking human gross deletion breakpoints (9), genomic inversions that distinguish the human from the chimpanzee genome (17), and DNA sequence tracts involved in pathological gene conversion events (18) have provided evidence for a wide ranging role for DNA secondary structure in promoting gross genomic rearrangements.…”

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confidence: 79%

Non-B DNA-forming Sequences and WRN Deficiency Independently Increase the Frequency of Base Substitution in Human Cells

Bacolla

Wang

Jain

et al. 2011

Journal of Biological Chemistry

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Although alternative DNA secondary structures (non-B DNA) can induce genomic rearrangements, their associated mutational spectra remain largely unknown. The helicase activity of WRN, which is absent in the human progeroid Werner syndrome, is thought to counteract this genomic instability. We determined non-B DNA-induced mutation frequencies and spectra in human U2OS osteosarcoma cells and assessed the role of WRN in isogenic knockdown (WRN-KD) cells using a supF gene mutation reporter system flanked by triplex-or Z-DNA-forming sequences. Although both non-B DNA and WRN-KD served to increase the mutation frequency, the increase afforded by WRN-KD was independent of DNA structure despite the fact that purified WRN helicase was found to resolve these structures in vitro. In U2OS cells, ϳ70% of mutations comprised single-base substitutions, mostly at G⅐C basepairs, with the remaining ϳ30% being microdeletions. The number of mutations at G⅐C base-pairs in the context of NGNN/ NNCN sequences correlated well with predicted free energies of base stacking and ionization potentials, suggesting a possible origin via oxidation reactions involving electron loss and subsequent electron transfer (hole migration) between neighboring bases. A set of ϳ40,000 somatic mutations at G⅐C base pairs identified in a lung cancer genome exhibited similar correlations, implying that hole migration may also be involved. We conclude that alternative DNA conformations, WRN deficiency and lung tumorigenesis may all serve to increase the mutation rate by promoting, through diverse pathways, oxidation reactions that perturb the electron orbitals of neighboring bases. It follows that such "hole migration" is likely to play a much more widespread role in mutagenesis than previously anticipated.The application of high resolution array comparative genomic hybridization techniques has revealed the frequent occurrence of DNA sequence motifs capable of forming alternative (non-B) DNA conformations (e.g. triplex, quadruplex, Z-DNA, cruciforms, slipped structures) at the breakpoint junctions of chromosomal alterations (gross deletions and duplications) associated with human genetic disease, including cystic fibrosis, mental retardation, and multiple congenital anomalies (1). These observations have served to extend the generality of previous work that aimed to elucidate the molecular mechanisms underlying recurrent translocations (2-6) and the genetic instability observed in many model systems (7-16), both of which were suggestive of a direct mutagenic role for non-B DNA. In the same vein, analyses of DNA sequence motifs flanking human gross deletion breakpoints (9), genomic inversions that distinguish the human from the chimpanzee genome (17), and DNA sequence tracts involved in pathological gene conversion events (18) have provided evidence for a wide ranging role for DNA secondary structure in promoting gross genomic rearrangements. Despite these recent advances, few studies (8, 11) have attempted to address systematically the extent of the influence ...

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“…Hairpin loops, unpaired nucleotides, slipped-strand structures, or other aberrant conformations may be recognized as damage signals by one or more DNA repair systems such as mismatch repair and nucleotide excision repair (38), which are ultimately responsible for changing the length of the repeat sequence (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

R loops stimulate genetic instability of CTG·CAG repeats

Lin

Dent

Wilson

et al. 2009

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

173

207

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Transcription stimulates the genetic instability of trinucleotide repeat sequences. However, the mechanisms leading to transcriptiondependent repeat length variation are unclear. We demonstrate, using biochemical and genetic approaches, that the formation of stable RNA · DNA hybrids enhances the instability of CTG · CAG repeat tracts. In vitro transcribed CG-rich repeating sequences, unlike AT-rich repeats and nonrepeating sequences, form stable, ribonuclease A-resistant structures. These RNA · DNA hybrids are eliminated by ribonuclease H treatment. Mutation in the rnhA1 gene that decreases the activity of ribonuclease HI stimulates the instability of CTG · CAG repeats in E. coli. Importantly, the effect of ribonuclease HI depletion on repeat instability requires active transcription. We also showed that transcription-dependent CTG · CAG repeat instability in human cells is stimulated by siRNA knockdown of RNase H1 and H2. In addition, we used bisulfite modification, which detects single-stranded DNA, to demonstrate that the nontemplate DNA strand at transcribed CTG · CAG repeats remains partially single-stranded in human genomic DNA, thus indicating that it is displaced by an RNA · DNA hybrid. These studies demonstrate that persistent hybrids between the nascent RNA transcript and the template DNA strand at CTG · CAG tracts promote instability of DNA trinucleotide repeats.RNA·DNA hybrids | transcription-induced instability | triplet repeats E xpansions of simple repeating sequences (microsatellites) are responsible for more than 20 human diseases (1). Moreover, instability of simple repeats (expansion as well as contraction) is observed throughout the genomes of all organisms studied, and it is considered an important source of genetic variation (2). The molecular basis of this unusual mutation mechanism has been studied extensively in the past 15 years using bacteria, yeast, flies, mice, and mammalian cells. Although these analyses uncovered several cis elements and trans-acting factors affecting repeat instability (3), a unifying, comprehensive model of the repeat expansion and contraction is lacking. Processes such as replication, recombination, and repair, which temporarily dissociate DNA complementary strands, strongly destabilize repeating sequences. Transient exposure of single-stranded DNA regions allows formation of non-B DNA structures in regions containing repeats. Virtually all current models of repeat instability incorporate non-B DNA structures as the proximate cause of instability (4, 5).Recently, transcription through tandem repeat sequences has emerged as an important factor promoting instability of repeat sequences (6-12). Although the synthesis of RNA does not change the length of a DNA template, it can lead to the formation of non-B DNA structures, as shown in E. coli, yeast, and higher organisms (7-10, 13). These secondary structures may interfere with the progress of RNA polymerase, calling into play various DNA repair processes, whose action leads to repeat expansion and contraction. In h...

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Models for chromosomal replication‐independent non‐B DNA structure‐induced genetic instability

Cited by 48 publications

References 163 publications

Repeat instability during DNA repair: Insights from model systems

Repeat instability during DNA repair: Insights from model systems

Non-B DNA-forming Sequences and WRN Deficiency Independently Increase the Frequency of Base Substitution in Human Cells

R loops stimulate genetic instability of CTG·CAG repeats

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