DNA damage-induced histone loss
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB14701 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR1519471_1.fastq.gz | Fastqsanger.gz | |||
| ERR1519471_2.fastq.gz | Fastqsanger.gz | |||
| ERR1519472_1.fastq.gz | Fastqsanger.gz | |||
| ERR1519472_2.fastq.gz | Fastqsanger.gz | |||
| ERR1519473_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 16 |
Similar Datasets
Project description:The eukaryotic genome is organized into chromatin, which constitutes the physiological template for DNA-dependent processes including replication, recombination, repair and transcription. Chromatin mediated transcription regulation involves histone modifications, chromatin remodeling and DNA methylation. However, the precise biological function of non-histone chromatin-associated proteins is still unclear. The high mobility group proteins are the most abundant non-histone chromatin-associated proteins. Here we combined proteomic, ChIP-seq and transcriptome data to decipher the mechanism of transcriptional regulation mediated by the high mobility group AT-hook protein 2 (HMGA2). We showed that HMGA2-induced transcription requires H2AX phosphorylation at S139 (H2AXS139ph; γ-H2AX), mediated by the kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrated the relevance of this mechanism within the biological context of TGFB1-signaling. Our results link H2AXS139ph, a marker for DNA damage, to transcription, which is a new function for this histone modification. The interplay between HMGA2, ATM and H2AX is a novel mechanism of transcription initiation. Chip-seq data of HMGA2, H2AXS139ph and ATM obtained from Mouse embryonic Fibroblast cells in wt and Ko of Hmga2
2015-11-04 | E-GEOD-63861 | biostudies-arrayexpress
Project description:Post-translational modifications (PTM) of chromatin control the genomic environment for transcription, DNA replication and repair in response to cell stimuli1–3. Replication stress in budding and fission yeasts leads to abundant acetylation of histone H3 on lysine-56 (H3K56ac)4–6, but only trace levels of H3K56ac are detected in human cells7,8, implying that other histone modifications promote a repair-permissive environment. In budding yeast, genetic interactions between histone H3 lysine-56 and serine-57 substitutions suggest a possible role for serine-57 (H3S57) in responses to replication poisons9. In this study, we identify a phosphorylated form of H3S57 (H3S57ph) using phosphoproteomics in replicating Xenopus egg extracts, and show that it is a highly conserved histone modification which promotes responses to DNA replication stress in human cells. A kinome screen and functional experiments identified Checkpoint kinase 1 (CHK1) as the H3S57ph kinase; CHK1 inhibition eliminates H3S57ph and arrests cells in S-phase. Induction of replication stress increases H3S57ph, while disrupting H3S57ph reduces stalling of replication forks upon replication stress, inducing DNA damage. We identified two distinct mechanisms of action. First, H3S57ph interacts with specific DNA repair proteins, notably Rad50. Second, atomistic molecular dynamics simulations of the nucleosome core particle and in vitro assays indicate that H3S57ph interacts with the unacetylated side-chain of K56, thus loosening DNA-histone contacts. Our results suggest that H3S57ph is an effector of CHK1 that assists in processing stalled replication forks by increasing nucleosome mobility and promoting interactions with repair machinery, thereby limiting DNA damage upon replication stress.
2022-02-10 | PXD011328 | Pride
Project description:The eukaryotic genome is organized into chromatin, which constitutes the physiological template for DNA-dependent processes including replication, recombination, repair and transcription. Chromatin mediated transcription regulation involves histone modifications, chromatin remodeling and DNA methylation. However, the precise biological function of non-histone chromatin-associated proteins is still unclear. The high mobility group proteins are the most abundant non-histone chromatin-associated proteins. Here we combined proteomic, ChIP-seq and transcriptome data to decipher the mechanism of transcriptional regulation mediated by the high mobility group AT-hook protein 2 (HMGA2). We showed that HMGA2-induced transcription requires H2AX phosphorylation at S139 (H2AXS139ph; γ-H2AX), mediated by the kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrated the relevance of this mechanism within the biological context of TGFB1-signaling. Our results link H2AXS139ph, a marker for DNA damage, to transcription, which is a new function for this histone modification. The interplay between HMGA2, ATM and H2AX is a novel mechanism of transcription initiation.
2015-11-04 | GSE63861 | GEO
Project description:Mutant ataxin-1 (Atxn1), which causes spinocerebellar ataxia type 1 (SCA1), binds to and impairs the function of high mobility group box 1 (HMGB1), a critical nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. In this study, we established that transgenic or virus vector-mediated supplementation of HMGB1 ameliorates motor dysfunction and elongates lifespan in mutant Atxn1 knock-in (Atxn1-KI) mice. We identified mitochondrial DNA damage repair by HMGB1 as a novel molecular basis for this effect, in addition to the mechanisms already associated with HMGB1 function, such as nuclear DNA damage repair and nuclear transcription. The dysfunction and the improvement of mitochondrial DNA damage repair functions are tightly associated with the exacerbation and rescue, respectively, of symptoms, supporting the involvement of mitochondrial DNA quality control by HMGB1 in SCA1 pathology. Moreover, we show that the rescue of Purkinje cell dendrites and dendritic spines by HMGB1 could be downstream effects. Although extracellular HMGB1 triggers inflammation mediated by toll-like receptor and receptor for advanced glycation end products, upregulation of intracellular HMGB1 does not induce such side effects. Thus, viral delivery of HMGB1 is a candidate approach by which to modify the disease progression of SCA1 even after its onset.
2015-01-05 | E-MTAB-2987 | biostudies-arrayexpress
Project description:we reported that in the absence of YTHDF2, spermatogonia showed significantly enhanced sensitivity to etoposide and promoted apoptosis, demonstrating that the importance of YTHDF2 in the etoposide-responsive DNA damage response (DDR). Multiple modifications involved in the DDR, some of which recruit repair factors to the sites of DNA damage. N6-methyladenosine (m6A) as a crucial component of the DNA damage repair system responding to DNA lesions. Meanwhile, H3K9me3 has been implicated in DDR, which provides site for DDR factors binding to DNA lesion. Importantly, ablation of Ythdf2 reduced SETDB1 and H3K9me3 levels, and SETDB1 overexpression qualitatively suppressed the DNA damage associated with YTHDF2 loss.
2023-12-30 | GSE217071 | GEO
Project description:YTHDF2 promotes DNA damage repair by positively regulating the histone methyltransferase SETDB1 in spermatogonia
| PRJNA896860 | ENA
Project description:Histone exchange assay in loss of DOT1
| PRJNA416910 | ENA
Project description:PARP inhibitors have exhibited efficacy in BRCA-proficient patients, further highlighting the necessity for a deeper understanding of PARP1 function and its inhibition in cancer therapy. Here, we unveil PIN2/TRF1-interacting telomerase inhibitor 1 (PINX1) as an uncharacterized PARP1-interacting protein that synergizes with PARP inhibitors upon its depletion across various cancer cell lines. Loss of PINX1 compromises DNA damage repair capacity upon etoposide treatment. The vulnerability of PINX1-deficient cells to etoposide and PARP inhibitors could be effectively restored by introducing either a full-length or a mutant form of PINX1 lacking telomerase inhibitory activity. Mechanistically, PINX1 is recruited to DNA lesions via PARP1, facilitating the downstream recruitment of the DNA repair factor XRCC1. In the absence of DNA damage, PINX1 constitutively binds to PARP1, promoting PARP1-chromatin association and transcription of specific DNA damage repair proteins, including XRCC1, and transcriptional regulators, including GLIS3. Collectively, our findings identify PINX1 as a multifaceted partner of PARP1, crucial for safeguarding cells against genotoxic stress and emerging as a potential candidate for targeted tumor therapy.
2024-08-21 | GSE256388 | GEO
Project description:Cirrhosis is a late stage of fibrosis that fatally impairs liver function. Unfortunately, genetic animal models mimicking human cirrhosis are lacking and the molecular mechanisms remain unknown. Here we report the first murine genetic model recapitulating clinical features of cirrhosis, which are induced by hepatocyte-specific elimination of microspherule protein 1 (MCRS1), a member of the non-specific lethal (NSL) and INO80 chromatin modifier complexes. Deregulation of bile acid (BA) transporter expression, revealed by proteomic analysis of MCRS1-depleted mouse livers, with pronounced downregulation of the Na+-taurocholate cotransporting polypeptide (NTCP), causes BA accumulation in liver sinusoids. Genetic ablation of the BA receptor FXR in hepatic stellate cells (HSCs) suppresses bile duct ligation (BDL)-induced fibrosis in mice. Moreover, in vitro experiments demonstrate that fibrotic marker expression is reduced in FXR-depleted HSCs cultured in conditioned medium containing high BAs from MCRS1-depleted hepatocytes. Additionally, hepatocytic MCRS1 overexpression increases their NTCP levels, and consequently protects mice against BDL-induced liver fibrosis. Deletion of a putative SANT domain in MCRS1, also revealed by protein sequence analysis and essential for histone H3 (H3) binding, disrupts H3/HDAC1 complex formation. This evicts MCRS1 and HDAC1 from their H3 anchoring sites and increases histone lysine acetylation of BA transporter genes, independently of the NSL or INO80 complexes. Taken together, our data reveal a previously unrecognized function of MCRS1 as a novel histone acetylation regulator that binds to H3, and recruits a novel chromatin-modifying complex that maintains gene expression homeostasis and liver health. Accordingly, loss of nuclear MCRS1 correlates with increased histone acetylation in human cirrhosis samples. Regulation of histone acetylation might thus be central to cirrhotic development.
2022-05-19 | PXD023026 | Pride
Project description:Targetted metabolomics in U2OS PRDX1 WT and PRDX1-/- While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential when cells are exposed to DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Subsequent analysis identified Peroxiredoxin 1, PRDX1, as fundamental for DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it is required to reduce DNA damage-induced nuclear reactive oxygen species levels. Moreover, PRDX1 controls aspartate availability, which is required for the DNA damage repair-induced upregulation of de novo nucleotide synthesis. Loss of PRDX1 leads to an impairment in the clearance of γΗ2ΑΧ nuclear foci, accumulation of replicative stress and cell proliferation defects, thus revealing a crucial role for PRDX1 as a DNA damage surveillance factor.
2022-07-19 | ST002234 | MetabolomicsWorkbench