Sites of instability in the human TCF3 (E2A) gene adopt G-quadruplex DNA structures in vitro

Williams, Jonathan; Fleetwood, Sara; Berroyer, Alexandra; Kim, Nayun; Larson, Erik D.

doi:10.3389/fgene.2015.00177

Cited by 20 publications

(31 citation statements)

References 55 publications

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“…Thus, G-quadruplexes could constitute physical barriers for the replication machinery [2], posing a serious threat to genome stability [160]. Consistently, in humans, fork stalling and genome instability associated with G4 motifs are linked to common translocation events associated with acute lymphoblastic leukemia [168]. …”

Section: Replication Barriers Associated With Repeat Dna and Protementioning

confidence: 99%

Regulation of DNA Replication through Natural Impediments in the Eukaryotic Genome

Gadaleta

Noguchi

2017

Genes

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All living organisms need to duplicate their genetic information while protecting it from unwanted mutations, which can lead to genetic disorders and cancer development. Inaccuracies during DNA replication are the major cause of genomic instability, as replication forks are prone to stalling and collapse, resulting in DNA damage. The presence of exogenous DNA damaging agents as well as endogenous difficult-to-replicate DNA regions containing DNA–protein complexes, repetitive DNA, secondary DNA structures, or transcribing RNA polymerases, increases the risk of genomic instability and thus threatens cell survival. Therefore, understanding the cellular mechanisms required to preserve the genetic information during S phase is of paramount importance. In this review, we will discuss our current understanding of how cells cope with these natural impediments in order to prevent DNA damage and genomic instability during DNA replication.

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Section: Replication Barriers Associated With Repeat Dna and Protementioning

confidence: 99%

Regulation of DNA Replication through Natural Impediments in the Eukaryotic Genome

Gadaleta

Noguchi

2017

Genes

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“…However, the extent to which they are involved in mediating mutations on a genome‐wide scale has not been fully ascertained. Indeed, the association of non‐B DNA‐forming sequences with genomic instability has been best established in the area of triplet repeat expansion diseases [Iyer et al., ; Zhao and Usdin, ], and in gross chromosomal abnormalities, both in the germline [Cooper et al., ; Verdin et al., ; You et al., ; Wu et al., ; Javadekar and Raghavan, ] and in cancer [De and Michor, ; Nambiar et al., ; Jeitany et al., ; Lu et al., ; Williams et al., ]. Filling this knowledge gap is of particular importance in the field of medical genetics, given the widespread occurrence of non‐B DNA‐forming repeats in the human and other mammalian genomes [Du et al., ].…”

Section: Introductionmentioning

confidence: 99%

A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

et al. 2015

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Missense/nonsense mutations and micro-deletions/micro-insertions of <21bp together represent ~76% of all mutations causing human inherited disease. Previous studies have shown that their occurrence is influenced by sequences capable of non-B DNA formation (direct, inverted and mirror repeats; G-quartets). We found that a greater than expected proportion (~21%) of both micro-deletions and micro-insertions occur within direct repeats and are explicable by slipped misalignment. A novel mutational mechanism, non-B DNA triplex formation followed by DNA repair, is proposed to explain ~5% of micro-deletions and microinsertions at mirror repeats. Further, G-quadruplex-forming sequences, direct and inverted repeats appear to play a prominent role in mediating missense mutations, whereas only direct and inverted repeats mediate nonsense mutations. We suggest a mutational mechanism involving slipped strand mispairing, slipped structure formation and DNA repair, to explain ~15% of missense and ~12% of nonsense mutations leading to the formation of perfect direct repeats from imperfect repeats, or to the extension of existing direct repeats. Similar proportions of missense and nonsense mutations were explicable by the mechanism of hairpin loop formation and DNA repair leading to the formation of perfect inverted repeats from imperfect repeats. The proposed mechanisms provide new insights into mutagenesis underlying pathogenic micro-lesions.

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“…Of particular note are G4-capable sequences enriched at oncogenes, where G4 structure formation may contribute to gene regulation and oncogenesis (9). G4 structures have been shown to form from guanine-repeat sequences at rearrangement sites, such as the HOX11 (10), BCL2 (11), and TCF3 (12) cancer-related genes.…”

Section: Introductionmentioning

confidence: 99%

G-quadruplex DNA structures can interfere with uracil glycosylase activityin vitro

Holton

Larson

2015

MUTAGE

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Genome sequences that contain tandem repeats of guanine can form stable four-stranded structures known as G-quadruplex, or G4 DNA. While the molecular mechanisms are not fully defined, such guanine-rich loci are prone to mutagenesis and recombination. Various repair pathways function to reduce the potential for genome instability by correcting base damage and replication errors; however, it is not yet fully defined how well these processes function at G4 DNA. One frequent form of base damage occurs from cytidine deamination, resulting in deoxyuracil and UG mismatches. In duplex and single-stranded DNA, uracil bases are recognised and excised by uracil glycosylases. Here, we tested the efficiency of uracil glycosylase activity in vitro on uracil bases located directly adjacent to guanine repeats and G4 DNA. We show that uracil excision by bacterial UDG and human hUNG2 is reduced at uracils positioned directly 5' or 3' of a guanine tetrad. Control reactions using oligonucleotides disrupted for G4 formation or reaction conditions that do not favour G4 formation resulted in full uracil excision activity. Based on these in vitro results, we suggest that folding of guanine-rich DNA into G4 DNA results in a DNA conformation that is resistant to uracil glycosylase-initiated repair and this has the potential to increase the risk of instability at guanine repeats in the genome.

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Sites of instability in the human TCF3 (E2A) gene adopt G-quadruplex DNA structures in vitro

Cited by 20 publications

References 55 publications

Regulation of DNA Replication through Natural Impediments in the Eukaryotic Genome

Regulation of DNA Replication through Natural Impediments in the Eukaryotic Genome

A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

G-quadruplex DNA structures can interfere with uracil glycosylase activityin vitro

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