Palindromes in DNA—A Risk for Genome Stability and Implications in Cancer

Miklenić, Marina Svetec; Svetec, Ivan‐Krešimir

doi:10.3390/ijms22062840

Cited by 23 publications

(28 citation statements)

References 127 publications

(161 reference statements)

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“…Irrespective of whether we consider microdeletions or gross deletions, the mechanisms underlying pathogenic deletions appear to be strongly influenced by the local DNA sequence environment (Kondrashov & Rogozin, 2004;Krawczak & Cooper, 1991). The role of non-B DNA structures in the formation of cancer-associated deletions, as well as deletions in the germline and in mitochondrial sequences, has been appreciated for some time (Bacolla et al, 2016(Bacolla et al, , 2019Damas et al, 2014;Dong et al, 2014;Fontana & Gahlon, 2020;Pabis, 2021;Svetec Miklenić & Svetec, 2021;Zhao et al, 2010). Such non-B DNA structures often have key regulatory functions in DNA replication and transcription but may also cause genomic instability (Lemmens et al, 2015;Zhao et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Distinct sequence features underlie microdeletions and gross deletions in the human genome

Stenson

Ball

et al. 2022

Human Mutation

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Microdeletions and gross deletions are important causes (~20%) of human inherited disease and their genomic locations are strongly influenced by the local DNA sequence environment. This notwithstanding, no study has systematically examined their underlying generative mechanisms. Here, we obtained 42,098 pathogenic microdeletions and gross deletions from the Human Gene Mutation Database (HGMD) that together form a continuum of germline deletions ranging in size from 1 to 28,394,429 bp. We analyzed the DNA sequence within 1 kb of the breakpoint junctions and found that the frequencies of non-B DNA-forming repeats, GC-content, and the presence of seven of 78 specific sequence motifs in the vicinity of pathogenic deletions correlated with deletion length for deletions of length ≤30 bp.Further, we found that the presence of DR, GQ, and STR repeats is important for the formation of longer deletions (>30 bp) but not for the formation of shorter deletions (≤30 bp) while significantly (χ 2 , p < 2E−16) more microhomologies were identified flanking short deletions than long deletions (length >30 bp). We provide evidence to support a functional distinction between microdeletions and gross deletions. Finally, we propose that a deletion length cut-off of 25-30 bp may serve as an objective means to functionally distinguish microdeletions from gross deletions.

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Section: Discussionmentioning

confidence: 99%

Distinct sequence features underlie microdeletions and gross deletions in the human genome

Stenson

Ball

et al. 2022

Human Mutation

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“…Therefore, when using Cas9-induced DSBs at individual sites to study regulation of DSB repair pathway choices, we should avoid generalization unless it is taken into consideration how Cas9-sgRNA interacts with its target and is released from it after DNA cleavage. In addition, repair of the three-ended DSBs provides an opportunity for the DNA ends of two sister chromatids to rejoin, not only creating a palindromic chromosome with two centromeres or no centromere [42,43], but also leaving the third end for potential translocation. Both dicentric and acentric palindromic chromosomes are unstable and serves as a potential source for chromothripsis and complex chromosomal rearrangements including large deletions and insertions at the target site [40][41][42][43]54].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, repair of the three-ended DSBs provides an opportunity for the DNA ends of two sister chromatids to rejoin, not only creating a palindromic chromosome with two centromeres or no centromere [42,43], but also leaving the third end for potential translocation. Both dicentric and acentric palindromic chromosomes are unstable and serves as a potential source for chromothripsis and complex chromosomal rearrangements including large deletions and insertions at the target site [40][41][42][43]54]. Therefore, this study identi es a potential mechanism underlying on-target chromosomal rearrangements previously detected in CRISPR/Cas9 genome editing [55][56][57][58][59].…”

Section: Discussionmentioning

confidence: 99%

Cas9-sgRNA target residence alters DNA double strand break repair pathway choices in CRISPR/Cas9 genome editing

Xie

Liu

Feng

et al. 2022

Preprint

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Given its different target-binding affinity and varying residence time after DNA cleavage, the Cas9-sgRNA complex that remains bound to cleaved DNA may influence DNA double strand break (DSB) repair pathway choices, contributing to highly heterogeneous mutations in genome editing. Here, we found that DSB repair pathway choices vary significantly at different sites for Cas9-induced DSBs. Reduced target-binding affinity of Cas9-sgRNA promotes a bias toward classical NHEJ (c-NHEJ), but inactivation of c-NHEJ aggravates off-target activities. By dislodging Cas9-sgRNA from the cleaved target, local DNA replication suppresses c-NHEJ in favor of other DSB repair pathways by altering DSB configuration and repair timing. It also results in sister chromatid fusion, which may promote chromosomal breakage-fusion-bridge cycles. This suggests that varying Cas9-sgRNA target-binding affinity or residence duration modulate DSB repair pathway choices for Cas9-induced DSBs and widen the mutational spectra in CRISPR/Cas9 genome editing.

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“…Our observations suggest that the M. oryzae genome is divided into genes needed for interaction with the environment similarly surrounded by house-keeping genes as described for the non-conserved regions in Fusarium graminearu m where these types of genes are overrepresented (Zhao et al, 2014). One of the most potential DNA-binding sites for the MoISW2 is a palindromic motif giving instability to the genome at this site (Ganapathiraju et al, 2020; Svetec Miklenić and Svetec, 2021) and characteristic of motifs for retrotransposons situated close to stress-related genes and avirulence genes (plant pathogen effectors with a difference in resistance against by cultivars, thus the cause of avirulence against these cultivars)(Yoshida et al, 2016). The authors also found that a gene linkage to transposons is connected with elevated mutation rates.…”

Section: Discussionmentioning

confidence: 99%

Whole genome regulatory effect ofMoISW2and consequences for the evolution of the rice plant pathogenic fungusMagnaporthe oryzae

Pie

Abubakar

Ali

et al. 2022

Preprint

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Isw2 is known to bind DNA, using a Myb-type DNA binding domain, and with another part of the protein interact with histones in the closest nucleosome to pull the two closest nucleosomes closer to the binding site using ATP. These bindings hinder these nucleosomes' sliding movements and affect histone tail modification and DNA methylation but give more space for sliding and access for transcription factors further away from the Isw2 DNA binding sites. In a previous paper, we have knocked out the Magnaporthe oryzae Isw2 protein and complemented it with a GFP-labelled construct. We found that the MoISW2 is needed, especially in the later necrotrophic stages of infection when the plant starts defending itself. Using published transcriptomic data, we have now found that MoISW2 is mainly co-regulated with Histone 4 (MoHIS4), which likely indicates that MoIsw2 predominately interacts with MoHis4. We performed a ChIP-seq experiment using MoIsw2-GFP to map the binding sites and investigated if the MoIsw2 regulates genes by the limited sliding type and if this regulation could be involved in pathogenicity regulation. Common motifs were found in the binding DNA sequences using MEME. Interestingly, these motifs were mainly intergenic, and a dominant palindrome motif was present in 200 sequences. We further performed an RNAseq for ΔMoisw2 compared with Ku80 background strain and used genes sorted in physical order on the supercontigs to determine the effect of the mutation on the regulation of the genes physically close to the MoIsw2 binding sites. The genes close to the binding site were more absolutely regulated in the ΔMoisw2 mutant. As nucleosomes are evenly distributed at roughly 200bp distance, there should be an interference pattern of regulation of genes centered around the MoIsw2 DNA binding site if the genes are roughly evenly distributed, which could be confirmed. We queried the NCBI database again and checked where the 200 palindromic sequences were found in the genome to investigate if MoIsw2 binds to any known structures in the DNA. The palindromic sequences were found in conserved retrotransposon elements that generally contain palindromes. Since these retrotransposon elements can move place, they can create new regulatory variations with MoIsw2. Many avirulence genes recognized by different host plant cultivars and typically vary in expression between pathogen isolates were close to the MoIsw2 DNA binding site. That could mean that mobile elements associated with some MoIsw2 DNA binding sites are involved in creating variations in the pathogenicity of different M. oryzae strains. To test this idea, we searched through the transcriptomic data of our strain (70-15) and another strain (98-05) for variation in AVR expression during infection and if differences in MoIsw2 binding could be the cause for this variation and it seems to be that. Finally, we found that most of the genes upregulated in the ΔMoisw2 mutant regulate biomass growth (DNA-binding and quality control and TFs overrepresented). In contrast, the ones downregulated have to do with mainly mitochondrial oxidative phosphorylation, oxidative stresses, and secondary metabolites. Similar results for enriched and depleted genes were found for all genes in our ChIP-seq data for genes closest to MoIsw2 binding. We conclude that MoIsw2 interaction with nucleosomes and binding to palindromic DNA in transposons located between genes creates a possibility for fast variation of offspring regulatory pattern without loss of genes through mutation and fast creation of M.oryzae strains with new cultivar host ranges in response to defenses by resistant cultivars and consequently a fast break of resistance. MoISW2 also seems to aid in the natural adaptation-directed fast evolution (NADFE) of M. oryzae, which is discussed as a new concept for Eukaryotes.

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Palindromes in DNA—A Risk for Genome Stability and Implications in Cancer

Cited by 23 publications

References 127 publications

Distinct sequence features underlie microdeletions and gross deletions in the human genome

Distinct sequence features underlie microdeletions and gross deletions in the human genome

Cas9-sgRNA target residence alters DNA double strand break repair pathway choices in CRISPR/Cas9 genome editing

Whole genome regulatory effect ofMoISW2and consequences for the evolution of the rice plant pathogenic fungusMagnaporthe oryzae

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