VID22 counteracts G-quadruplex-induced genome instability
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ABSTRACT:
PROVIDER: PRJNA731119 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14585681.fastq.gz | Fastqsanger.gz | |||
| SRR14585682.fastq.gz | Fastqsanger.gz |
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Project description:Genome instability is a condition characterized by the accumulation of various genetic alterations and is a hallmark of cancer cells. To uncover new genes and cellular pathways controlling the levels of endogenous DNA damage and affecting genome integrity, we exploited a Synthetic Genetic Array (SGA)-based screen in yeast. Among the positive genes, we identified VID22, a gene previously reported to be involved in DNA double-strand break repair. We found that vid22Δ cells exhibit chronic DNA damage response activation, show increased levels of increased endogenous DNA damage and accumulate DNA aberrations in sequences displaying high probabilities of forming G-quadruplexes (G4-DNA). If not resolved, these non-canonical DNA secondary structures can block the progression of both DNA and RNA polymerases and correlate with chromosome fragile sites. We show that Vid22 in vitro and in vivo binds directly to and protects DNA at G4-containing regions both in vitro and in vivo. In particular, loss of VID22 causes an increase in gross chromosomal rearrangement (GCR) events dependent on G-quadruplex forming sequences. We also demonstrate that the absence of Vid22 causes defects in the correct maintenance of G4-DNA rich elements, such as telomeres and mtDNA, and hypersensitivity to the G4-stabilizing ligand TMPyP4. We thus propose that Vid22 is directly involved in genome integrity maintenance as a novel regulator of G4 metabolism.
2021-11-08 | GSE174688 | GEO
Project description:Genome instability is a condition characterized by the accumulation of genetic alterations and is a hallmark of cancer cells. To uncover new genes and cellular pathways affecting endogenous DNA damage and genome integrity, we exploited a Synthetic Genetic Array (SGA)-based screen in yeast. Among the positive genes, we identified VID22, reported to be involved in DNA double-strand break repair. vid22Δ cells exhibit increased levels of endogenous DNA damage, chronic DNA damage response activation and accumulate DNA aberrations in sequences displaying high probabilities of forming G-quadruplexes (G4-DNA). If not resolved, these DNA secondary structures can block the progression of both DNA and RNA polymerases and correlate with chromosome fragile sites. Vid22 binds to and protects DNA at G4-containing regions both in vitro and in vivo. Loss of VID22 causes an increase in gross chromosomal rearrangement (GCR) events dependent on G-quadruplex forming sequences. Moreover, the absence of Vid22 causes defects in the correct maintenance of G4-DNA rich elements, such as telomeres and mtDNA, and hypersensitivity to the G4-stabilizing ligand TMPyP4. We thus propose that Vid22 is directly involved in genome integrity maintenance as a novel regulator of G4 metabolism.
| S-EPMC8682794 | biostudies-literature
Project description:Genome instability is a hallmark of most human cancers and is exacerbated following cellular exposure to exogenous/endogenous chemicals that can promote replication stress, activation of low-fidelity DNA repair pathways and DNA damage. However, the effects drugs/chemicals have in promoting nuclear genome instability and mutagenesis in normal cells as early biomarkers of cancer risk remains unexplored. Here, we present the Drug-induced Genome Instability Test (DiGIT), a systems level approach that identifies the genome instability risk of drugs/chemicals by measuring activated mutagenic DNA repair and resulting structural rearrangements at the gene level in mammalian genomes. We found drugs previously classified as being non-genotoxic by classic genotoxicity assays, induced genome instability in proliferative mammalian cells, including normal human mammary epithelial fibroblasts (HMECs), bone marrow, duodenum and CD19+ B cells. 53BP1 (a key mediator of mutagenic DNA repair) foci were increased in a dose-dependent manner in HMECs following treatment with compounds known to induce genomic instability (low-dose aphidicolin, duvelisib, idelalisib and hydralazine) and compounds suspected of causing genomic instability based on carcinogenicity outcomes (amiodarone). Non-genotoxic compounds (mannitol, alosteron, diclofenac and zonisamide) not associated with cancer risk did not induce effects on the recruitment of 53BP1. To evaluate genomic instability in vivo, Sprague Dawley rats were treated with cyclophosphamide, a known anti-cancer therapeutic. Short-term treatment resulted in drug-induced somatic translocations and deletions at genes associated with cancer risk in proliferating normal cells from the bone marrow and duodenum. Collectively, DiGIT comprising cell- and whole-genome sequencing-based approaches can aid in de-risking genotoxicity and/or cancer liabilities of therapeutic and complement the current genetic toxicology battery.
2019-09-18 | PRJEB34208 | EVA
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Project description:The G-quadruplex is an alternative DNA structural motif that is considered to be functionally important in the mammalian genome. Herein, we address the hypothesis that G-quadruplex structures can exist within double-stranded genomic DNA using a G-quadruplex-specific probe. An engineered antibody is employed to enrich for DNA containing G-quadruplex structures, followed by deep sequencing to detect and map G-quadruplexes at high resolution in genomic DNA from human breast adenocarcinoma cells. Our high sensitivity structure-based pull-down strategy enables the isolation of genomic DNA fragments bearing a single as well as multiple G-quadruplex structures. Stable G-quadruplex structures are found in sub-telomeres, gene bodies and gene regulatory regions. For a sample of identified target genes, we show that G-quadruplex stabilizing ligands can modulate transcription. These results confirm the existence of G-quadruplex structures and their persistence in human genomic DNA. Four independent libraries have been enriched in DNA G-quadruplex structures using a G-quadruplex-specific probe. One genomic input library was sequenced as control. Deep-sequencing of these libraries allowed the mapping of G-quadruplexes on the genome.
2013-05-08 | E-GEOD-45241 | biostudies-arrayexpress
Project description:G-quadruplex (G4) structures are secondary structures that can form in guanine-rich single stranded DNA sequences. These play important roles in biological processes such as regulation of gene expression but can also pose challenges to DNA replication and lead to genome instability. The SMARCA4 (BRG1) subunit of the SWI/SNF chromatin remodelling complexes has been identified as a G4 binding protein, and evidence suggests that this interaction can promote SWI/SNF-dependent gene expression. SMARCA4 is frequently misregulated in cancer, where genome instability is common, but whether there is an impact of SMARCA4 on G4 stability was not known. Here, we show that SMARCA4 prevents genome instability at G4s. Mapping unrepaired DNA breaks reveals that these preferentially co-localise with G4 forming structures in SMARCA4-deficient cells. Moreover, using whole genome sequencing approaches, we find that misrepair events in SMARCA4 deficient cells are more likely to map to G4 forming sequences. Consistent with this, SMARCA4 deficient cells show sensitivity to the G4 ligand pyridostatin and defective pyridostatin-induced DNA damage responses. Notably, similar patterns of G4-associated mutations were found in patients with SMARCA4-mutant tumours when compared with control patient groups. These findings suggest that SMARCA4 plays a crucial role in maintaining stability at G4 motifs. This insight provides valuable information about the functional significance of G4 structures and their interaction with SMARCA4, particularly in the context of cancer.
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Project description:G-rich DNA sequences can form four-stranded G-quadruplex (G4) secondary structures and are linked to fundamental biological processes such as transcription, replication and telomere maintenance. G4s are also implicated in promoting genome instability, cancer and other diseases. Here, we describe a detailed G4 ChIP-seq method that robustly enables the determination of G4 structure formation genome-wide in chromatin. This protocol adapts traditional ChIP-seq for the detection of DNA secondary structures through the use of a G4-structure-specific phage display antibody with refinements in chromatin immunoprecipitation followed by high-throughput sequencing. Beginning with chromatin isolation and antibody preparation the entire protocol can be completed in less than 1 week including computational analysis.
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