Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis

Poetsch, Anna R.; Boulton, Simon J.; Luscombe, Nicholas M.

doi:10.1101/168153

Cited by 31 publications

(42 citation statements)

References 67 publications

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“…We ruled out that this is caused by the MMR deficiency and found support for a pathway that protects exons over introns thus masking the signatures of TCR. A similar finding was made in human cells where less oxidative DNA damage accumulates in exons than in introns — possibly due to a favorable repair (33). If a similar process is occurring in flies, as our data suggest, we propose that the global repair pathway of nucleotide excision repair is favoring exons over introns.…”

Section: Discussionsupporting

confidence: 69%

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Transcription-coupled repair inDrosophila melanogasteris independent of the mismatch repair pathway

Törmä¹,

Burny²,

Nolte³

et al. 2020

Preprint

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1Transcription-coupled repair (TCR) removes base damage on the transcribed strand of a gene to 2 ensure a quick resumption of transcription. Based on the absence of key enzymes for TCR and 3 empirical evidence, TCR was thought to be missing in Drosophila melanogaster. The recent 4 demonstration of TCR in S2 cells raises the question about the involved genes. Since the 5 mismatch repair (MMR) pathway serves a central role in TCR, at least in Escherichia coli, we 6 studied the mutational signatures in flies with a deletion of the MMR gene spellchecker1 (spel1), 7 a MutS homolog. Whole-genome sequencing of mutation accumulation (MA) lines obtained 7,345 8 new single nucleotide variants (SNVs) and 5,672 short indel mutations, the largest data set from 9 an MA study in D. melanogaster. Based on the observed mutational strand-asymmetries, we 10 conclude that TCR is still active without spel1. The operation of TCR is further confirmed by a 11 negative association between mutation rate and gene expression. Surprisingly, the TCR 12 signatures are detected for introns, but not for exons. We propose that an additional exon-specific 13 repair pathway is masking the signature of TCR. This study presents the first step towards 14 understanding the molecular basis of TCR in Drosophila melanogaster. 15

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Section: Discussionsupporting

confidence: 69%

“…DNA repair and damage processes can differ between exons and introns (32, 33). We therefore analyzed exons and introns separately.…”

Section: Resultsmentioning

confidence: 99%

Transcription-coupled repair inDrosophila melanogasteris independent of the mismatch repair pathway

Törmä¹,

Burny²,

Nolte³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Hypoxia and oxidative damage are likely to also affect the genome in ways that do not directly impact gene expression. Indeed, the distribution of oxidative DNA damage sites varies across the genome following stress such that TEs and active chromatin regions are enriched for DNA damage, while promoters are depleted (Poetsch et al, 2018). We found enrichment for TEs, specifically Alu SINE elements, in DARs.…”

Section: Mechanisms Behind Response Genes and Dynamic Eqtlsmentioning

confidence: 75%

Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

Ward

Banovich²,

Sarkar³

et al. 2020

Preprint

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One life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived of oxygen. To study inter-individual differences in response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels in four culturing conditions that correspond to normoxia, hypoxia and short or long-term reoxygenation. We characterized thousands of gene regulatory changes as the cells transition between conditions. Using available genotypes, we identified 1,573 genes with a cis expression quantitative locus (eQTL) in at least one condition, as well as 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of genes with dynamic eQTLs is associated with complex traits and disease. Our data demonstrate how dynamic genetic effects on gene expression, which are likely relevant for disease, can be uncovered under stress.

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“…This discovery raises the intriguing question about whether endogenous oxidative or AP site damage occurs in a targeted or site-specific manner. Although a few recent studies have shown a region-specific distribution of DNA damage (67,68), additional high-resolution (single-base) mapping of base damage in the genome is warranted.…”

Section: Discussionmentioning

confidence: 99%

Endogenous oxidized DNA bases and APE1 regulate the formation of G-quadruplex structures in the genome

Roychoudhury

Pramanik

Harris

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Formation of G-quadruplex (G4) DNA structures in key regulatory regions in the genome has emerged as a secondary structure-based epigenetic mechanism for regulating multiple biological processes including transcription, replication, and telomere maintenance. G4 formation (folding), stabilization, and unfolding must be regulated to coordinate G4-mediated biological functions; however, how cells regulate the spatiotemporal formation of G4 structures in the genome is largely unknown. Here, we demonstrate that endogenous oxidized guanine bases in G4 sequences and the subsequent activation of the base excision repair (BER) pathway drive the spatiotemporal formation of G4 structures in the genome. Genome-wide mapping of occurrence of Apurinic/apyrimidinic (AP) site damage, binding of BER proteins, and G4 structures revealed that oxidized base-derived AP site damage and binding of OGG1 and APE1 are predominant in G4 sequences. Loss of APE1 abrogated G4 structure formation in cells, which suggests an essential role of APE1 in regulating the formation of G4 structures in the genome. Binding of APE1 to G4 sequences promotes G4 folding, and acetylation of APE1, which enhances its residence time, stabilizes G4 structures in cells. APE1 subsequently facilitates transcription factor loading to the promoter, providing mechanistic insight into the role of APE1 in G4-mediated gene expression. Our study unravels a role of endogenous oxidized DNA bases and APE1 in controlling the formation of higher-order DNA secondary structures to regulate transcription beyond its well-established role in safeguarding the genomic integrity.

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Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis

Cited by 31 publications

References 67 publications

Transcription-coupled repair inDrosophila melanogasteris independent of the mismatch repair pathway

Transcription-coupled repair inDrosophila melanogasteris independent of the mismatch repair pathway

Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

Endogenous oxidized DNA bases and APE1 regulate the formation of G-quadruplex structures in the genome

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