Midas v5
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REPOSITORIES: ENA
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Project description:Multiple replication abnormalities cause cells lacking BRCA2 to enter mitosis with under-replicated DNA and to activate mitotic DNA synthesis (MiDAS). However, the precise position of these MiDAS sites, as well as their origin, remains unknown. Here we labelled mitotic nascent DNA and performed high-throughput sequencing to identify at high-resolution the sites where MiDAS occurs in the absence of BRCA2. This approach revealed 150 genomic loci affected by MiDAS, which map within regions replicating during early S-phase and are therefore distinct from the aphidicolin-induced common fragile sites. Moreover, these sites largely localise near early firing origins and within genes transcribed in early S, suggesting that they stem from transcription-replication conflicts (TCRs). Inhibiting transcription with 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) during early S-phase abrogates MiDAS. Strikingly, MiDAS sites co-localise with genomic loci where R-loops form in unchallenged conditions, suggesting that R-loop accumulation caused by BRCA2 inactivation leads to DNA lesion which are repaired by MiDAS. RAD52 is required in this process, as its abrogation in BRCA2-deficient cells reduces the rate of MiDAS and causes DNA damage accumulation in G1. Furthermore, MiDAS sites triggered by BRCA2 inactivation are hotspots for genomic rearrangement in BRCA2-mutated breast tumours. These results indicate that BRCA2 acts in early S-phase to protect TRC- and R-loop-induced DNA lesions, thereby preventing them from becoming a source of genomic instability and tumorigenesis.
2022-08-01 | GSE196163 | GEO
Project description:DNA replication stress is an established driver of cancer-associated chromosomal rearrangements. Replication stress perturbs the duplication of late-replicating loci and activates a mitotic DNA repair pathway (termed MiDAS) for completion of replication. We here investigated RAD51-independent MiDAS.
2022-06-27 | GSE196278 | GEO
Project description:The microbial database of activated sludge - Denmark (MiDAS-DK)
| PRJEB8105 | ENA
Project description:This 133-node Boolean regulatory network model reproduces mitochondrial dynamics during cell cycle progression (hyper-fusion at the G1/S boundary, fission in mitosis), apoptosis (fission and dysfunction) and glucose starvation (reversible hyper-fusion), as well as MiDAS in response to SIRT3 knockdown or oxidative stress and the protective role of NAD+ or external pyruvate. These features are in addition to the cell cycle-related phenotypes reproduced by the Sizek et al model that served as our starting point. Testable predictions (new): a) In cell lines with low basal p21 expression known to pre-commit to the next division in early mitosis of their current cycle, a subset of cells respond to glucose withdrawal by arresting with 4N DNA content but losing their internal G2 state (i.e. Cyclin A/B expression), and undergo endo-reduplication upon glucose re-exposure. b) In a subset of glucose-starved cells that pass the G2/M checkpoint with hyperfused mitochondria, mitotic fragmentation can be sufficiently delayed to cause spindle assembly defects and mitotic catastrophe. c) Quiescent cells are less susceptible to ROS-induced MiDAS due to FoxO-mediated PINK1 expression, which blocks MFN1/2 from inducing hyperfusion. d) Boosting NAD+ levels in MiDAS cells that have not yet established deep senescence (2-3 days post induction) can reverse their fate.
2024-08-26 | MODEL2312140001 | BioModels
Project description:The experimental project studied a MIDAS adhesin minus mutant of predatory bacterium B. bacteriovorus.The predatory bacterium normally invades and lives inside E.coli bacteria, rounding them up to form a two-bacterial structure, called a bdelloplast, and killing the E.coli from the inside. However the MIDAS mutant predator failed to invade in 10% of cases due to one of its (many) attachment/invasion mechanisms being absent. We enriched and purified the 10% of bdelloplasts which did not have an invaded predator inside, by Percoll gradient centrifugation. Although these bdelloplasts did not have an invaded predator they were still rounded and dead. We sent the bdelloplast sample for total protein content analysis at the Oxford Advanced Proteomics Facility. We found that although the bdelloplasts areE.coli cells they also contain secreted Bdellovibrio proteins that normally an invading wild type Bdellovibrio is known to secrete into their prey, during invasion. This suggests that a short-lived failed attachment allowed the Bdellovibrio to secrete in predatory proteins , even though it failed to enter the E.coli, and that those predatory proteins alone were enough to round and kill it.
2024-03-18 | PXD050423 | Pride
Project description:The ribosome maturation factor Rea1 (or Midasin) catalyses the removal of assembly factors from large ribosomal subunit precursors and to promotes their export from the nucleus to the cytosol. Rea1 consists of nearly 5000 amino-acid residues and belongs to the AAA+ protein family. It consists of a ring of six AAA+ domains from which the ≈ 1700 amino-acid residue linker emerges that is subdivided into stem, middle and top domains. A flexible and unstructured D/E rich region connects the linker top to a MIDAS (metal ion dependent adhesion site) domain, which is able to bind the assembly factor substrates. Despite its key importance for ribosome maturation, the Rea1 mechanism driving assembly factor removal by Rea1 is still poorly understood. Here we demonstrate that the Rea1 linker 30 is essential for assembly factor removal. It rotates and swings towards the AAA+ ring following a complex remodelling scheme involving nucleotide independent as well as nucleotide dependent steps. ATP-hydrolysis is required to engage the linker with the AAA+ ring and ultimately with the AAA+ ring docked MIDAS domain. The interaction between the linker top and the MIDAS domain allows direct force transmission for assembly factor removal. To evaluate the conformational changes and spatial proximities in presence or absence of nucleotides we carried out XL-MS experiments using PhoX on purified Rea1 in presence of ATPgS, AMP-PNP or in Apo state (in XL triplicates each).
2024-07-29 | PXD053636 | Pride
Project description:Trichormus variabilis V5 strain:V5 Genome sequencing and assembly
| PRJNA591934 | ENA
Project description:Technologies for measuring 3D genome topology are increasingly important for studying mechanisms of gene regulation, for genome assembly and for mapping of genome rearrangements. We developed multiplex-GAM, a faster and more affordable version of Genome Architecture Mapping (GAM), a ligation-free technique to map chromatin contacts genome-wide. We applied multiplex-GAM to Mouse ES cells.
2022-06-13 | GSE166380 | GEO
Project description:Technologies for measuring 3D genome topology are increasingly important for studying mechanisms of gene regulation, for genome assembly and for mapping of genome rearrangements. We developed multiplex-GAM, a faster and more affordable version of Genome Architecture Mapping (GAM), a ligation-free technique to map chromatin contacts genome-wide. We applied multiplex-GAM to Mouse ES cells.
2022-06-13 | GSE166379 | GEO
Project description:Changes in DNA methylation are associated with normal cardiogenesis, while altered methylation patterns can occur in congenital heart disease. Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) and promote locus-specific DNA demethylation. Here we characterize stage-specific methylation dynamics and the function of TETs during directed differentiation of human embryonic stem cells (hESCs) to cardiomyocyte (CM) fate. No defect is observed using isogenic TET2, TET3 or TET2/3 double knockout lines, while TET1 knockout lines display a significant decrease in capacity to generate CTNT+ CMs. Moreover, hESCs in which all three TET genes are inactivated (TET TKO hESCs) fail entirely to generate CMs. TET-deficient cells display altered mesoderm patterning and defective cardiac progenitor specification. Genome-wide methylation analysis shows that TETs are required first to maintain hypomethylation of early regulatory genes, and subsequently for demethylation of cardiac structural genes. Mechanistically, TET knockout causes promoter hypermethylation of genes encoding WNT inhibitors, leading to hyperactivated WNT signaling and defects in cardiac mesoderm patterning. TET activity is also needed to maintain hypomethylated status and expression of NKX2-5 for subsequent cardiac progenitor specification. Finally, loss of TETs causes a set of cardiac structural genes to fail to be demethylated at the cardiac progenitor stage. Our data demonstrate key roles for TET proteins to control methylation dynamics at sequential steps during human cardiac development.
2021-12-07 | GSE186847 | GEO