2020
DOI: 10.1093/nar/gkaa483
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Topoisomerase II contributes to DNA secondary structure-mediated double-stranded breaks

Abstract: Abstract DNA double-stranded breaks (DSBs) trigger human genome instability, therefore identifying what factors contribute to DSB induction is critical for our understanding of human disease etiology. Using an unbiased, genome-wide approach, we found that genomic regions with the ability to form highly stable DNA secondary structures are enriched for endogenous DSBs in human cells. Human genomic regions predicted to form non-B-form DNA induced gross chromosomal r… Show more

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Cited by 34 publications
(50 citation statements)
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“…In the ancestral sequences, the smaller decrease in observed free energy around ① is reflective of pre-event potential for structural formation in a subset of events, suggesting that some events may involve hairpin-mediated quasipalindrome-to-palindrome conversion as in the original mechanism proposed for bacteria [ 22 ]. Regardless of ancestral stability, the spontaneous creation of sequence regions capable of forming stable secondary structures is of note, as small regions of stable structure play a role in several biological processes [ 42 , 43 ], and regions of similarly stable structure can cause fork collapse, DSB formation and trigger genome instability [ 44 , 45 ].…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…In the ancestral sequences, the smaller decrease in observed free energy around ① is reflective of pre-event potential for structural formation in a subset of events, suggesting that some events may involve hairpin-mediated quasipalindrome-to-palindrome conversion as in the original mechanism proposed for bacteria [ 22 ]. Regardless of ancestral stability, the spontaneous creation of sequence regions capable of forming stable secondary structures is of note, as small regions of stable structure play a role in several biological processes [ 42 , 43 ], and regions of similarly stable structure can cause fork collapse, DSB formation and trigger genome instability [ 44 , 45 ].…”
Section: Resultsmentioning
confidence: 99%
“…We calculated minor groove width, helical twist and propeller twist in these regions, as well as for 100,000 uniform random sampled 1001nt sequences from across all GRCh38 chromosomes, using the DNAShapeR package [ 45 ], which is based on the method of [ 69 ] for predicting DNA structural information. This approach utilises a pentamer sliding window to calculate each feature as determined through Monte Carlo simulations, accounting for sequence context of the focal nucleotide within the window.…”
Section: Methodsmentioning
confidence: 99%
“…Genome-wide analyses of G4 motifs in human cells indicate that these structures are highly correlated with RNA-Pol II pausing sites and R-loop-forming regions, two different factors promoting RNA-Pol II arrests and transcription-dependent DNA breaks ( Puget et al, 2019 ; Chen et al, 2017 ; Eddy et al, 2011 ). Additionally, the formation of highly stable DNA secondary structures, such as G4, has been shown to promote the formation of DNA topoisomerase 2 (TOP2)-mediated DNA breaks ( Szlachta et al, 2020 ). Interestingly, recent studies demonstrate a major contribution of TOP2 activity in the generation of DSBs in highly transcribed genes ( Canela et al, 2019 ; Gittens et al, 2019 ; Gothe et al, 2019 ).…”
Section: Introductionmentioning
confidence: 99%
“…In the ancestral sequences, the smaller decrease in observed free energy around ① is reflective of pre-event potential for structural formation in a subset of events, suggesting that some events may involve hairpin-mediated quasipalindrome-to-palindrome conversion as in the original mechanism proposed for bacteria (22). Regardless of ancestral stability, the spontaneous creation of sequence regions capable of forming stable secondary structures is of note, as small regions of stable structure play a role in several biological processes (39, 40), and regions of similarly stable structure can cause fork collapse, DSB formation and trigger genome instability (41, 42).…”
Section: Resultsmentioning
confidence: 99%