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Homo sapiens strain:Human Embryonic Kidney cells 293

ABSTRACT: Analysis of the effects of human wild-type TREX1 and 3' frameshift mutant TREX1 (RVCL TREX1) expression on CRISPR/Cas9-induced DSB repair.

PROVIDER: PRJDB17735 | ENA |

REPOSITORIES: ENA

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Dataset's files

Source:

			Action	DRS
	DRR538915_subreads.fastq.gz	Fastqsanger.gz
	DRR538916_subreads.fastq.gz	Fastqsanger.gz
	DRR538917_subreads.fastq.gz	Fastqsanger.gz
	DRR538918_subreads.fastq.gz	Fastqsanger.gz
	DRR538919_subreads.fastq.gz	Fastqsanger.gz

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Homo sapiens

Project description:Analysis of the effects of human wild-type TREX1 and 3' frameshift mutant TREX1 (RVCL TREX1) expression on CRISPR/Cas9-induced DSB repair by short amplicon sequencing.

| PRJDB17744 | ENA

NeonGreen-POLQ knock-in in Human embryonic kidney 293 cells VS Human embryonic kidney 293 cells

Project description:Replication stress (RS) can lead to the formation of DNA double strand breaks (DSBs) and threatens genomic stability. Homologous recombination (HR) pathway is essential to prevent RS and repairs associated DSBs. Upon excessive RS or HR deficiency, DSBs can persist in mitosis, wherein DNA damage response and DSB repair are inhibited. Thus, the fate of DSBs remaining or arising in mitosis remains poorly understood. Here we unwind two distinct roles of the polymerase theta (Polθ) in the maintenance of genomic stability. First, by mass spectrometry and foci screening we show that, in interphase, Polθ interacts with HR proteins and its recruitment to IR-induced DSBs is highly dependent of HR pathway. Secondly, we identify a novel role of the Polθ in counteracting the deleterious effect of DSBs in mitosis. Contrariwise to its interphase recruitment, Polθ recruitment to mitotic DSBs is HR-independent and triggered by mitotic kinases activities. In response to RS or HR deficiency, Polθ localizes to DSBs throughout mitosis and forms nuclear bodies in the G1 daughter cells. In addition, Polθ localizes to centromeres and acentric fragments and activates the mitotic checkpoint. Conversely, Polθ deficiency leads to premature anaphase onset, resulting in an accumulation of mitotic abnormalities. Strikingly, the specific inhibition of Polθ in mitosis kills HR-deficient cells, identifying mitotic Polθ function as its key role in maintaining genome integrity. Our results pinpoint to the mitotic Polθ-mediated replication stress response pathway as a unique vulnerability of cancer cells, with great potential for further investigation.

2023-09-18 | PXD029585 | Pride

RNA-seq of H9 hESC line carrying shRB expression cassette, and H9 hESC line carrying shRB expression cassette in addition to CRISPR/Cas9-mediated nonsense mutations on RBL1 and RBL2

Project description:In order to investigate the roles of retinoblastoma family genes during early human development, mutant H9 human embryonic stem cells were generated. Frameshift mutations were introduced in RBL1 and RBL2 genes using the CRISPR/Cas9 technology, and then the shRNA-expression cassette to knockdown RB upon tetracycline treatment was integrated. These cells were cultured in definitive endoderm differentiation conditions for 3 or 6 days with/without tetracycline.

2022-06-20 | E-MTAB-11109 | biostudies-arrayexpress

Project description:Cas9/sgRNA DSB repair of kmoRG

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Project description:Cas9/sgRNA DSB repair of 1pc.kmoRGB

| PRJNA1250599 | ENA

Probing the direct differences in TREX1 gene modification in mice.

Project description:We constructed Trex1-/-, Trex1D18N, Trex1p212fs mice by CRISPR-Cas9 technology. Four genotypes of MEFS, WT, Trex1-/-, Trex1D18N, Trex1p212fs were obtained by isolating 13.5-day mouse embryos, and then second generation MEFs were collected for RNA-seq analysis to explore the differences between cells.

2023-07-12 | GSE226512 | GEO

scRNAseq of heterozygous HNF1B-mutant vs non-mutant kidney organoids derived from human embryonic stem cells

Project description:Human embryonic stem cell (hESC) line Man-13 was edited by CRISPR resulting in a hESC line carrying a heterozygous frameshift mutation with a premature stop codon in exon-1 of the HNF1B gene ([p.Val61Argfs*18]), functionally equivalent to a heterozygous whole-gene deletion. Kidney organoids were then created by differentiation (as per Takasato et al, 2015; Bantounas et al, 2018; Bantounas et al 2021) of this line and an isogenic non-mutant control line. Single-cell RNAseq (scRNAseq) was then performed on day-25 of differentiation to identify transcriptomic differences, as well as differences in identity and numbers of the cell populations comprising the organoids, with the aim of mechanistically explaining developmental aberrations observed in patients with mutations in this gene.

2024-04-30 | E-MTAB-13500 | biostudies-arrayexpress

Biological Plasticity Rescues Target Activity in CRISPR Knock Outs

Project description:Systematic investigation of residual protein expression in frameshift KO mutations derived from CRISPR-Cas9 in clonal cell lines

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Project description:Cas9/sgRNA DSB repair of BR-KmoEx4 Lig4-

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Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans

Project description:Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the liver, brain, kidney and retina. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3’-5’ DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of the radiation injury, we reasoned that nuclear TREX1 promotes DNA damage. Here, we show that RVCL-associated TREX1 variants cause DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a new mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.

2024-05-30 | PXD051905 | Pride

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