Effects of Replication and Transcription on DNA Structure-Related Genetic Instability

Wang, Guliang; Vásquez, Karen M.

doi:10.3390/genes8010017

Cited by 71 publications

(64 citation statements)

References 158 publications

(192 reference statements)

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“…For example, at CAG repeats, R‐loop‐dependent cytosine deamination occurs, leading to BER processing and APE1/Apn1‐dependent breaks . Nucleotide excision repair (NER) nucleases XPF and XPG can also process R‐loop DNA structures, as well as cruciform and triplex DNA structures, resulting in DSBs and genomic instability . Given the interplay between DNA structure and R‐loop formation, it is possible that these two mechanisms are working together to cause fragility, or they could be independent events.…”

Section: Secondary Structures and Their Relation To Other Theories Fomentioning

confidence: 99%

The role of fork stalling and DNA structures in causing chromosome fragility

Kaushal

Freudenreich

2019

Genes Chromosomes & Cancer

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Alternative non‐B form DNA structures, also called secondary structures, can form in certain DNA sequences under conditions that produce single‐stranded DNA, such as during replication, transcription, and repair. Direct links between secondary structure formation, replication fork stalling, and genomic instability have been found for many repeated DNA sequences that cause disease when they expand. Common fragile sites (CFSs) are known to be AT‐rich and break under replication stress, yet the molecular basis for their fragility is still being investigated. Over the past several years, new evidence has linked both the formation of secondary structures and transcription to fork stalling and fragility of CFSs. How these two events may synergize to cause fragility and the role of nuclease cleavage at secondary structures in rare and CFSs are discussed here. We also highlight evidence for a new hypothesis that secondary structures at CFSs not only initiate fragility but also inhibit healing, resulting in their characteristic appearance.

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Section: Secondary Structures and Their Relation To Other Theories Fomentioning

confidence: 99%

The role of fork stalling and DNA structures in causing chromosome fragility

Kaushal

Freudenreich

2019

Genes Chromosomes & Cancer

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“…DNA carries the genetic information that living organisms decrypt to efficiently ensure their developmental programs and their response/adaption to environmental cues. Exposure to biotic/abiotic stresses can directly or indirectly induce the formation of DNA damage such as bases modifications, DNA breaks, alterations of DNA structure all interfering with DNA replication and transcription (Wang and Vasquez, 2017). Due to their lifestyle, photosynthetic organisms use the beneficial effect of sunlight (Eberhard et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Photodamage repair pathways contribute to the accurate maintenance of the DNA methylome landscape upon UV exposure

Graindorge

Cognat

Berens

et al. 2019

Preprint

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Plants are exposed to the damaging effect of sunlight that induces DNA photolesions. In order to maintain genome integrity, specific DNA repair pathways are mobilized. Upon removal of UV-induced DNA lesions, the accurate re-establishment of epigenome landscape is expected to be a prominent step of these DNA repair pathways. However, it remains poorly documented whether DNA methylation is accurately maintained at photodamaged sites and how photodamage repair pathways contribute to the maintenance of genome/methylome integrities.Using genome wide approaches, we report that UV-C irradiation leads to asymmetric DNA methylation changes. We identified that the specific DNA repair pathways involved in the repair of UV-induced DNA lesions, Direct Repair (DR) and Global Genome Repair (GGR), prevent the excessive alterations of DNA methylation landscape. Moreover, we identified that UV-C irradiation induced chromocenter reorganization and that photodamage repair factors control this dynamics. The methylome changes rely on misregulation of maintenance, de novo and active DNA demethylation pathways highlighting that molecular processes related to genome and methylome integrities are closely interconnected. Importantly, we identified that photolesions are sources of DNA methylation changes in both, constitutive and facultative heterochromatin. This study unveils that DNA repair factors, together with small RNA, act to accurately maintain both genome and methylome integrities at photodamaged silent genomic regions, strengthening the idea that plants have evolved sophisticated interplays between DNA methylation dynamics and DNA repair. Availability of data and materialsWGBS, DNA-seq and small RNA-seq raw data generated in this work are publicly accessible through the GEO registration number : GSE132750. Authors' contributionsSG and VC performed bioinformatics. PJtoB performed cytogenetics, developed the automated image analysis program with JMu and analyzed the data. SG, VC, PJtoB and JMu wrote the methods section. JM designed experiments, prepared the biological samples, analyzed the data and wrote the manuscript. All authors read and approved the final manuscript.

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“…The global degree of intertwining of the two DNA strands in the duplex, or equivalently over-or underwinding of the helix is referred to supercoiling 4,5 . In vivo, the degree of supercoiling affects cellular processes including gene expression 6 , enzyme binding 7 and genome organization 8 . Supercoiling is maintained in a state of dynamic homeostasis through the action of a class of enzymes termed topoisomerases, which counteract physiological processes of DNA metabolism such as transcription and replication that alter DNA topology 9 .…”

Section: Introductionmentioning

confidence: 99%

Coarse-Grained Modelling of DNA Plectoneme Pinning in the Presence of Base-Pair Mismatches

Desai

Brahmachari

Marko

et al. 2019

Preprint

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Damaged or mismatched DNA bases result in the formation of physical defects in doublestranded DNA. In vivo, defects in DNA must be rapidly and efficiently repaired to maintain cellular function and integrity. Defects can also alter the mechanical response of DNA to bending and twisting constraints, both of which are important in defining the mechanics of DNA supercoiling. Here, we use coarse-grained molecular dynamics (MD) simulation and supporting mean-field theory to study the effect of mismatched base pairs on DNA supercoiling. The coarse-grained approach reproduces experimentally observed deterministic plectoneme pinning at the mismatch under conditions of relatively high force (> 2 pN) and high salt concentration (> 0.5 M NaCl). Under physiologically relevant conditions of lower force (0.3 pN) and lower salt concentration (0.2 M NaCl), we find that plectoneme pinning becomes probabilistic and the pinning probability increases with the mismatch size. The simulation results broadly agree with existing statistical mechanical mean-field theoretical predictions for the high force-high salt regime. The coarse-grained simulation framework, validated with experimental results and supported by the theoretical predictions, provides a way to study the effect of defects on DNA supercoiling and the dynamics of supercoiling in molecular detail.

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Effects of Replication and Transcription on DNA Structure-Related Genetic Instability

Cited by 71 publications

References 158 publications

The role of fork stalling and DNA structures in causing chromosome fragility

The role of fork stalling and DNA structures in causing chromosome fragility

Photodamage repair pathways contribute to the accurate maintenance of the DNA methylome landscape upon UV exposure

Coarse-Grained Modelling of DNA Plectoneme Pinning in the Presence of Base-Pair Mismatches

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