Genome wide mapping of DNA lesions by Repair Assisted Damage Detection sequencing – RADD-Seq
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE166843 | GEO | 2021/02/17
REPOSITORIES: GEO
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Project description:Protecting the integrity of their genome is critical to all species. The surveillance and maintenance of the genome of every organism is orchestrated by a highly regulated combination of DNA damage response and specific DNA repair pathways. Two of these critical pathways are base excision repair (BER) and ribonucleotide excision repair (RER). Here, we investigate the phylogenetic diversity in the recognition and repair of three well-established DNA lesions, primarily repaired by BER or RER: 1) 8-oxoguanine, 2) an abasic site, and 3) incorporated ribonucleotide in DNA in E. coli, B. subtilis, H. salinarum, T. brucei, T. thermophila, S. cerevisiae, S. pombe, C. elegans, human HeLa and HEK293 cells, A. thaliana, and Z. mays. Using quantitative mass spectrometry, we identified 337 enriched interactors across these species. Of these proteins, 140 were previously characterized to be involved in DNA repair, and 39 proteins were newly identified due to their homology to previously studied repair proteins. For 10 of the 11 species, we identify unique, uncharacterized proteins that lack homology to any protein within the included 11 species. Our study emphasizes strong crosstalk between RER and BER and highlights the evolutionary conservation of this cross recognition across all domains of life.
2023-07-20 | PXD036040 | Pride
Project description:Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g., 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti- cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause lost mitochondrial function leading to S- phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g., PARP1, as potential targets for cancer treatment. _x000B_
2020-08-07 | GSE155782 | GEO
Project description:Shells of pearl oyster are natural biominerals with remarkable properties and can be repaired after damage, which are regulated by biomacromolcules especially shell matrix proteins (SMPs). Identifying SMPs is critical for further understanding the process. Although proteomic methods have been used to reveal the complex protein mixture in mature shells, the proteomics of repaired shells after shell damage have not been reported before. Here, we studied the SMPs of the repaired shells (prismatic layers) 5-10 days after shell damage in Pinctada fucata by integrating transcriptomics and proteomics and compared the microstructure difference between repaired and mature shells. Although the repaired shells are calcite, similar to mature shells, the microstructure of repaired shells has holes in the center of prisms with irregular and curved edges. In total, we found 49 SMPs from the repaired shells including some proteins only existing in mature nacreous layers. Peroxidase-like protein and beta-N-acetylhexosaminidase may be important players in repaired shells. In addition, they have the capability to affect CaCO3 crystallization process in vitro, altering the packing and reducing the crystallinity of crystals. This study could improve our understanding of shell repair process and lay the foundation for studying SMPs-controlled biomineralization.
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Project description:UV-induced DNA damage is the major carcinogen of skin cancer. We developed HS-Damage-seq to map UV damage with unprecedented sensitivity and resolution in human cells. While the distribution of UV-induced damage are mainly determined by sequence context and essentially uniform throughout the genome, transcription factors can affect damage formation at specific positions. With time-course experiments, we observed changes in damage distribution at particular genomic loci and chromatin states, which reflects the nucleotide excision repair preferences and complements the repair maps by XR-seq. Our results demonstrated that while initial damage is uniformly distributed, they are heterogeneously repaired throughout the genome. The combination of damage and repair maps provides a holistic perspective of UV damage and repair in the human genome.
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Project description:Active DNA demethylation in mammals involves TET-mediated iterative oxidation of 5-methylcytosine (5mC)/5-hydroxymethylcytosine (5hmC) and subsequent excision repair of highly oxidized cytosine bases 5-formylcytosine (5fC)/5-carboxylcytosine (5caC) by Thymine DNA glycosylase (TDG). However, quantitative and high-resolution analysis of active DNA demethylation activity remains challenging. Here we describe M.SssI methylase-assisted bisulfite sequencing (MAB-seq), a method that directly maps 5fC/5caC at single-base resolution. Genome-wide MAB-seq allows systematic identification of 5fC/5caC in Tdg-depleted embryonic stem cells, thereby generating a base-resolution map of active DNA demethylome. A comparison of 5fC/5caC and 5hmC distribution maps indicates that catalytic processivity of TET enzymes correlates with local chromatin accessibility. MAB-seq also reveals strong strand asymmetry of active demethylation within palindromic CpGs. Integrating MAB-seq with other base-resolution mapping methods enables quantitative measurement of cytosine modification states at key transitioning steps of active demethylation pathway, and reveals a regulatory role of 5fC/5caC excision repair in active DNA demethylation cascade. Analysis of 5fC/5caC excision repair-dependent active DNA demethylome by MAB-seq in mouse embryonic stem cells.
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Project description:Ultraviolet C radiation (UVC) damages the nuclear and mitochondrial genomes; this damage is repaired in the nuclear but not mitochondrial genome. Ethidium bromide (EtBr) inhibits mitochondrial DNA replication. We were interested in the transcriptomic response to exposure to UVC, EtBr, and the combination. The UVC exposure protocol results in a high level of mitochondrial DNA damage, and a low level of nuclear DNA damage (because of repair).
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Project description:To interrogate single-base resolution 6mA sites in the genome-wide, we develop DA-6mA-seq (DpnI-Assisted N6-methylAdenine sequencing), an optimized sequencing method taking advantage of restriction enzyme DpnI, which exclusively cleaves methylated adenine sites. We find DpnI also recognizes other sequence motifs besides the canonical GATC restriction sites, largely expanding the application range of this method. DA-6mA-seq requires less starting material and lower sequencing depth than previous methods, but achieves higher sensitivity, providing a good strategy to identify 6mA in large genome with a low abundance of 6mA. We rebuild the 6mA maps of Chlamydomonas by DA-6mA-seq and then apply this method to another two eukaryotic organisms, Plasmodium and Penicillium. Further analysis reveals most 6mA sites are symmetric at various sequence contexts, suggesting 6mA may function as a new heritable epigenetic mark in eukaryotes. A new sequencing method is developed to detect 6mA in eukaryotes
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Project description:Critical DNA repair pathways become deranged during cancer development. This vulnerability may be exploited with DNA-targeting chemotherapy. Topoisomerase II inhibitors induce double-strand breaks which are detrimental to the cell, if not repaired. This repair process requires high-fidelity functional homologous recombination or error-prone non-homologous recombination. If either of these pathways is targeted, the compensatory pathway may rescue the cells and induce treatment resistance. c-Abl is a protein tyrosine kinase that is involved in cell differentiation, cell division, cell adhesion, and stress response including DNA damage induced stress. Here we used a low dose topoisomerase II inhibitor mitoxantrone to induce DNA damage and c-Abl kinase inhibitor imatinib in combination and studied the drug effects at transcriptomic level. The microarray data suggests that DNA repair, particularly homologous recombination, is downregulated together with alterations in cell cycle regulation. The data prompted to further validation assays on functional level which are shown in the original publication.
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