Non-B DB v2.0: a database of predicted non-B DNA-forming motifs and its associated tools

Cer, Regina Z.; Donohue, Duncan; Mudunuri, Uma; Temiz, Nuri A.; Loss, Michael; Starner, Nathan J.; Halusa, Goran N.; Volfovsky, Natalia; Yi, Ming; Luke, Brian T.; Bacolla, Albino; Collins, Jack; Stephens, Robert M.

doi:10.1093/nar/gks955

Cited by 139 publications

(133 citation statements)

References 16 publications

(18 reference statements)

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“…We were able to sequence rare telomere-genomic fusions from LIG3 −/− :LIG4 −/− cells, reinforcing the notion of the coincidence of fusion foci with DNA replication, since LIG1 is the most rational protagonist mediating these LIG4-independent inter-chromosomal events (Arakawa et al 2012;Lu et al 2016). Further support arises from our finding of a conspicuous and significant association of LIG3 −/− :LIG4 −/− junctionproximal sequence with non-B DNA structures (Cooper et al 2011;Cer et al 2013) and a trend toward increased coincidence with fragile sites for LIG4 −/− junctions, implicating replication fork-stalling (Vissers et al 2009;Minca and Kowalski 2011;Ozeri-Galai et al 2011;Mizuno et al 2013) as a determinant of chromosome breakage and/or fusion. The A-NHEJ DNA polymerase theta also functions at the earliest stages of DNA replication and may, therefore, play a role in the introduction of the residual templated insertions resolved in these LIG4-deficient cells (Fernandez-Vidal et al 2014).…”

Section: Discussionsupporting

confidence: 77%

“…4B,C), indicating that repetitive DNA content alone does not confer a predisposition for the ultimate fusion ligation. We next investigated junction-proximal sequence context and discovered a unique and significant enhancement (sixfold over WT; P ≤ 0.001) in the incidence of non-B DNA structures (Cer et al 2013) within 500 bp of LIG3 −/− :LIG4 −/− inter-chromosomal fusion junctions (Supplemental Fig. 4D).…”

Section: A-and C-nhej Of Dysfunctional Human Telomeresmentioning

confidence: 99%

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Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

et al. 2016

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Telomeres shorten with each cell division and can ultimately become substrates for nonhomologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. We have characterized more than 1400 telomere fusion events at the single-molecule level, using a combination of high-throughput sequence analysis together with experimentally induced telomeric double-stranded DNA breaks. We show that a single chromosomal dysfunctional telomere can fuse with diverse nontelomeric genomic loci, even in the presence of an otherwise stable genome, and that fusion predominates in coding regions. Fusion frequency was markedly increased in the absence of TP53 checkpoint control and significantly modulated by the cellular capacity for classical, versus alternative, nonhomologous end joining (NHEJ). We observed a striking reduction in inter-chromosomal fusion events in cells lacking DNA ligase 4, in contrast to a remarkably consistent profile of intra-chromosomal fusion in the context of multiple genetic knockouts, including DNA ligase 3 and 4 doubleknockouts. We reveal distinct mutational signatures associated with classical NHEJ-mediated inter-chromosomal, as opposed to alternative NHEJ-mediated intra-chromosomal, telomere fusions and evidence for an unanticipated sufficiency of DNA ligase 1 for these intra-chromosomal events. Our findings have implications for mechanisms driving cancer genome evolution.

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Section: Discussionsupporting

confidence: 77%

Section: A-and C-nhej Of Dysfunctional Human Telomeresmentioning

confidence: 99%

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

et al. 2016

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“…(6) Non-B DNA (combined length of each class in base pairs). The Non-B DB v2.0 annotation was used in this analysis (Cer et al 2013). The classes of non-B DNA used were: A phased repeat, direct repeat, G-quadruplex motif, inverted repeat, mirror repeat, short tandem repeat, and Z DNA motif.…”

Section: Correlation Between Elongation Rate and Gene Featuresmentioning

confidence: 99%

Rate of elongation by RNA polymerase II is associated with specific gene features and epigenetic modifications

et al. 2014

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The rate of transcription elongation plays an important role in the timing of expression of full-length transcripts as well as in the regulation of alternative splicing. In this study, we coupled Bru-seq technology with 5,6-dichlorobenzimidazole 1-b-D-ribofuranoside (DRB) to estimate the elongation rates of over 2000 individual genes in human cells. This technique, BruDRB-seq, revealed gene-specific differences in elongation rates with a median rate of around 1.5 kb/min. We found that genes with rapid elongation rates showed higher densities of H3K79me2 and H4K20me1 histone marks compared to slower elongating genes. Furthermore, high elongation rates had a positive correlation with gene length, low complexity DNA sequence, and distance from the nearest active transcription unit. Features that negatively correlated with elongation rate included the density of exons, long terminal repeats, GC content of the gene, and DNA methylation density in the bodies of genes. Our results suggest that some static gene features influence transcription elongation rates and that cells may alter elongation rates by epigenetic regulation. The BruDRB-seq technique offers new opportunities to interrogate mechanisms of regulation of transcription elongation.

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“…To clarify whether the breakpoints were associated with repeat sequences or known rearrangement-inducing DNA features, we analyzed a 150-bp region on either side of the breakpoints using Repeatmasker (http://www.repeatmasker.org), palindrome (http:// emboss.bioinformatics.nl/cgi-bin/emboss/palindrome), and non-B database (https://nonb-abcc.ncifcrf.gov/). The non-B motifs analyzed were A-phased repeats, direct repeats, G-quadruplex motifs, inverted repeats, mirror repeats, short tandem repeats, and Z-DNA motifs [Cer et al, 2013].…”

Section: Molecular Analysismentioning

confidence: 99%

Xp22.31 Microdeletion due to Microhomology-Mediated Break-Induced Replication in a Boy with Contiguous Gene Deletion Syndrome

Nagai

Shima²,

Kamimura³

et al. 2017

Cytogenet Genome Res

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The Xp22.31 region is characterized by a low frequency of interspersed repeats and a low GC content. Submicroscopic deletions at Xp22.31 involving STS and ANOS1 (alias KAL1) underlie X-linked ichthyosis and Kallmann syndrome, respectively. Of the known microdeletions at Xp22.31, a common approximately 1.5-Mb deletion encompassing STS was ascribed to nonallelic homologous recombination, while 2 ANOS1-containing deletions were attributed to nonhomologous end-joining. However, the genomic bases of other microdeletions within the Xp22.31 region remain to be elucidated. Here, we identified a 2,735,696-bp deletion encompassing STS and ANOS1 in a boy with X-linked ichthyosis and Kallmann syndrome. The breakpoints of the deletion were located within Alu repeats and shared 2-bp microhomology. The fusion junction was not associated with nucleotide stretches, and the breakpoint-flanking regions harbored no palindromes or noncanonical DNA motifs. These results indicate that microhomology-mediated break-induced replication (MMBIR) can cause deletions at Xp22.31, resulting in contiguous gene deletion syndrome. It appears that interspersed repeats without other known rearrangement-inducing DNA features or high GC contents are sufficient to stimulate MMBIR at Xp22.31.

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Non-B DB v2.0: a database of predicted non-B DNA-forming motifs and its associated tools

Cited by 139 publications

References 16 publications

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

Rate of elongation by RNA polymerase II is associated with specific gene features and epigenetic modifications

Xp22.31 Microdeletion due to Microhomology-Mediated Break-Induced Replication in a Boy with Contiguous Gene Deletion Syndrome

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