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.
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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.
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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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Project description:G-quadruplexes (G4s) and R-loops are non-canonical DNA structures that can play regulatory functions of basic nuclear processes and can trigger DNA damage and genome instability. We here show that specific G4 ligands can stabilize G4s and simultaneously increase R-loop levels in human cancer cells likely by spreading DNA:RNA heteroduplexes to adjacent regions containing G4 structures. DNA cleavage and DNA damage response induced by G4 ligands were rescued by overexpression of exogenous RNaseH1 in cancer cells independently of BRCA2 status. The data thus show that R-loops are involved in the induction of DNA damage by chemical G4 stabilization. In addition, G4 ligands trigger the formation of micronuclei, particularly in BRCA2-silenced cancer cells, in an R-loop dependent manner. Our results uncover the mechanism of genome instability caused by G4 ligands and can open to the development of unexpected anticancer strategies using G4-targeted agents.
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