Genome-wide maps of double strand breaks after siRNA knockdown of DDX41 in HCT116 cells
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ABSTRACT:
PROVIDER: PRJNA759271 | ENA |
REPOSITORIES: ENA
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Project description:We report the first genome-wide mapping of fragility hotspots after siRNA-mediated knockdown of the DEAD-box helicase DDX41 in HCT116 cells using sBLISS. DDX41 defficient cells display elevated levels of genomic instability. sBLISS analysis revealed that hotspots for genomic instability in the absence of DDX41 are located around the transcription start site of transcribed genes.
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Project description:Doxorubicin is a widely used chemotherapeutic drug that intercalates between DNA base-pairs and posions Topoisomerase II, although the mechanistic basis for cell killing remains speculative. Here we show that both anthracyclines and Topoisomerase II poison cause enhanced DNA double-strand breaks around CpG island promoters of active genes genome-wide. We propose that torsion-based enhancement of nucleosome turnover exposes promoter DNA, ultimately causing DNA breaks around promoters that contributes to cell killing. We have analyzed mouse squamous cell carcinoma cells treated with doxorubicin, aclarubicin and etoposide. The direct in situ Breaks Labeling, Enrichment on Streptavidin (BLESS, PMID 23503052) method was used for mapping DNA double-strand breaks genome-wide.
2015-01-31 | E-GEOD-62927 | biostudies-arrayexpress
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Project description:Genome-wide maps of double-strand breaks
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Project description:Transcription can pose a threat to genomic stability through the formation of R-loops that obstruct the progression of replication forks. R-loops are three-stranded nucleic acid structures formed by an RNA-DNA hybrid with a displaced non-template DNA strand. We developed RDProx to identify proteins that regulate R-loops in human cells. RDProx relies on the expression of the hybrid-binding domain (HBD) of Ribonuclease H1 (RNaseH1) fused to the ascorbate peroxidase (APEX2), which permits mapping of the R-loop proximal proteome using quantitative mass spectrometry. We associated R-loop regulation with different cellular proteins and identified a role of the tumor suppressor DEAD box protein 41 (DDX41) in opposing R-loop-dependent genomic instability. Depletion of DDX41 resulted in replication stress, double strand breaks and increased inflammatory signaling. Furthermore, DDX41 opposes accumulation of R-loops at gene promoters and its loss leads to upregulated expression of TGFβ and NOTCH signaling genes. Germline loss-of-function mutations in DDX41 lead to predisposition to acute myeloid leukemia (AML) in adulthood. We propose that accumulation of co-transcriptional R-loops, associated gene expression changes and inflammatory response contribute to the development of familial AML with mutated DDX41.
2021-11-25 | PXD024517 | Pride
Project description:High concentration of NaCl increases DNA breaks both in cell culture and in vivo. The breaks remain elevated as long as NaCl concentration remains high and are rapidly repaired when the concentration is lowered. Repair of the breaks after NaCl is reduced is accompanied by formation of foci containing phosphorylated H2AX (γH2AX), which occurs around DNA double-strand breaks and contributes to their repair. By chromatin immunoprecipitation using anti-γH2AX antibody, followed by massive parallel sequencing (ChIP-Seq), we find that during repair of double–strand breaks induced by high NaCl, γH2AX is predominantly localized to regions of the genome devoid of genes (“gene deserts”), indicating that the high NaCl-induced double-strand breaks are located there. Localization to gene deserts helps explain why the DNA breaks are less harmful than are the random breaks induced by genotoxic agents such as UV radiation, ionizing radiation and oxidants. We propose that the universal presence of NaCl around animal cells has directly influenced the evolution of the structure of their genomes.
2011-11-21 | GSE32882 | GEO
Project description:Doxorubicin is a widely used chemotherapeutic drug that intercalates between DNA base-pairs and posions Topoisomerase II, although the mechanistic basis for cell killing remains speculative. Here we show that both anthracyclines and Topoisomerase II poison cause enhanced DNA double-strand breaks around CpG island promoters of active genes genome-wide. We propose that torsion-based enhancement of nucleosome turnover exposes promoter DNA, ultimately causing DNA breaks around promoters that contributes to cell killing.
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Project description:High concentration of NaCl increases DNA breaks both in cell culture and in vivo. The breaks remain elevated as long as NaCl concentration remains high and are rapidly repaired when the concentration is lowered. Repair of the breaks after NaCl is reduced is accompanied by formation of foci containing phosphorylated H2AX (M-NM-3H2AX), which occurs around DNA double-strand breaks and contributes to their repair. By chromatin immunoprecipitation using anti-M-NM-3H2AX antibody, followed by massive parallel sequencing (ChIP-Seq), we find that during repair of doubleM-bM-^@M-^Sstrand breaks induced by high NaCl, M-NM-3H2AX is predominantly localized to regions of the genome devoid of genes (M-bM-^@M-^\gene desertsM-bM-^@M-^]), indicating that the high NaCl-induced double-strand breaks are located there. Localization to gene deserts helps explain why the DNA breaks are less harmful than are the random breaks induced by genotoxic agents such as UV radiation, ionizing radiation and oxidants. We propose that the universal presence of NaCl around animal cells has directly influenced the evolution of the structure of their genomes. ChIP-Seq experiment to find locations of M-NM-3H2AX in mouse genome
2011-11-21 | E-GEOD-32882 | biostudies-arrayexpress
Project description:In relation with the study of the meiotic dynamic of H3K4 methylation, we determined the meiotic Double Strand Breaks (DSB) profiles of wild-type and set1∆ cells.
2008-11-01 | GSE12879 | GEO