Ontology highlight
ABSTRACT:
PROVIDER: PRJNA827119 | ENA |
REPOSITORIES: ENA
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Project description:The eukaryotic RNA processing factor Y14 participates in double-strand break (DSB) repair via its RNA-dependent interaction with the non-homologous end-joining (NHEJ) complex. We identified the long non-coding RNA HOTAIRM1 as a candidate that mediates this interaction. HOTAIRM1 localized to DNA damage sites induced by ionizing radiation. Depletion of HOTAIRM1 delayed the recruitment of DNA damage response and repair factors to DNA lesions and reduced DNA repair efficiency. Identification of the HOTAIRM1 interactome revealed a large set of RNA processing factors including mRNA surveillance factors. The surveillance factors Upf1 and SMG6 localized to DNA damage sites in a HOTAIRM1-dependent manner. Depletion of Upf1 or SMG6 increased the level of DSB-induced non-coding transcripts at damaged sites, indicating a pivotal role for Upf1/SMG6-mediated RNA degradation in DNA repair. We conclude that HOTAIRM1 serves as an assembly scaffold for both DNA repair and RNA processing factors that act in concert to repair DSBs.
2023-05-10 | PXD034470 | Pride
Project description:Radiotherapy has become a main treatment for patients with nasopharyngeal carcinoma (NPC), who often develop residual or recurrent tumors due to radioresistance. The lncRNA HOTAIRM1 plays crucial roles in the formation and development of various cancers, but the interaction between HOTAIRM1 and radioresistant NPC remains unclear. In this study, we evaluated the potential of HOTAIRM1 as a biomarker of NPC radioresistance. Proliferation, apoptosis, DNA damage, and RNA-seq analyses were conducted to examine the mechanisms by which HOTAIRM1 contributes to NPC radioresistance, and in vivo experiments were performed using nude mice. Our findings indicated that HOTAIRM1 levels were upregulated in radioresistant NPC tissues and cell lines. High HOTAIRM1 expression was associated with increased NPC cell proliferation, decreased apoptosis, and decreased cellular DNA damage after radiotherapy. Mechanistically, HOTAIRM1 promoted NPC radioresistance by increasing SLC7A11 stability and expression through METTL3-mediated m6A demethylation. Additionally, high HOTAIRM1 expression decreased SLC7A11-associated ferroptosis. Our findings demonstrate that HOTAIRM1 promotes METTL3-mediated m6A methylation to increase SLC7A11 expression and stability, thereby inhibiting ferroptosis to trigger NPC radioresistance. This novel molecular mechanism underlying the role of HOTAIRM1 in the regulation of radioresistant NPC may aid in the identification of biomarkers and therapeutic targets for the treatment of radioresistant NPC.
2023-04-12 | GSE229333 | GEO
Project description:Glioblastoma is the most common malignant primary brain tumor. Clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNA (lncRNA) alterations may contribute to glioblastoma pathogenesis and potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was analyzed in multiple glioblastoma gene expression data sets for associations with prognosis and IDH mutation and MGMT promoter methylation status. The role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, less invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses and determination of reactive oxygen species (ROS) levels revealed impaired mitochondrial function and increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2) as a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
2022-01-19 | PXD020141 | Pride
Project description:Glioblastoma is the most common malignant primary brain tumor. Clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNA (lncRNA) alterations may contribute to glioblastoma pathogenesis and potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was analyzed in multiple glioblastoma gene expression data sets for associations with prognosis and IDH mutation and MGMT promoter methylation status. The role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, less invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses and determination of reactive oxygen species (ROS) levels revealed impaired mitochondrial function and increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2) as a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
2020-06-10 | GSE152147 | GEO
Project description:Various modes of DNA repair counteract genotoxic DNA double-strand breaks (DSBs) to maintain genome stability. Recent findings suggest that the human DNA damage response (DDR) utilises damage-induced small RNA for efficient repair of DSBs. However, production and processing of RNA is poorly understood. Here we show that localised induction of DSBs triggers phosphorylation of RNA polymerase II (RNAPII) on carboxy-terminal domain (CTD) residue tyrosine-1 in an Mre11-Rad50-Nbs1 (MRN) complex-dependent manner. CTD Tyr1-phosphorylated RNAPII synthetises, strand-specific, damage-responsive transcripts (DARTs). DART synthesis occurs via formation of transient RNA-DNA hybrid (R-loop) intermediates. Impaired R-loop formation attenuates DART synthesis, impairs recruitment of repair factors and delays the DDR. Collectively, we provide mechanistic insight in RNA-dependent DSB repair.
2019-02-04 | GSE96825 | GEO
Project description:Transcriptional profiling of human fibroblast cells after DNA damage with Camptothecin or Etoposide or Neocarzinostatin Upon DNA damage, the DNA damage response (DDR) elicits a complex signaling cascade, which includes the induction of multiple non-coding RNA species. Recently long non-coding RNAs (lncRNAs) have been shown to contribute to DDR by regulating gene expression. However, very little is known about the role that lncRNAs play in regulating DNA Repair. Using a genome-wide microarray screen we identified a novel ubiquitously expressed lncRNA, DDSR1 (DNA damage-sensitive RNA 1), which is induced upon DNA damage by several DNA double-strand break (DSB) agents.
2015-09-01 | GSE67062 | GEO
Project description:Transcriptional profiling of human fibroblast cells after DNA damage with Camptothecin or Etoposide or Neocarzinostatin Upon DNA damage, the DNA damage response (DDR) elicits a complex signaling cascade, which includes the induction of multiple non-coding RNA species. Recently long non-coding RNAs (lncRNAs) have been shown to contribute to DDR by regulating gene expression. However, very little is known about the role that lncRNAs play in regulating DNA Repair. Using a genome-wide microarray screen we identified a novel ubiquitously expressed lncRNA, DDSR1 (DNA damage-sensitive RNA 1), which is induced upon DNA damage by several DNA double-strand break (DSB) agents. Two-condition experiment, Control vs. DNA damage human fibroblast cells. No Replicates, DNA damage was induced with either Camptothecin or Etoposide or Neocarzinostatin, Total RNA or Nuclear RNA was profiled.
2015-09-01 | E-GEOD-67062 | biostudies-arrayexpress
Project description:To investigate the target genes of HOTAIRM1 in glioma cells, we conducted a lncRNA + mRNA expression microarray analysis to identify novel HOTAIRM1 regulating genes. Three glioma cell lines U87MG, T98G and A172 stably knockdown HOTAIRM1 were used as the experiments models. We conservatively established a minimum of 2-fold difference between shHOTAIRM1 (knockdown HOTAIRM1) and shNT (control group), and identified 10 up-regulated and 22 down-regulated genes that met the threshold in all cell lines.
2021-12-26 | GSE192627 | GEO
Project description:The repair of DNA double strand breaks (DSBs) has recently been shown to depend not only on protein function but also on RNA. In particular, the processing of a long damage-induced RNA into small damage induced RNAs (diRNAs) has been a focus of interest. Given that the RNA exosome has been shown in Drosophila and human cells to participate in DSB repair, we investigated whether the catalytic components EXOSC10 and DIS3 have a function in diRNA biogenesis in human cells.
2019-04-10 | GSE113109 | GEO
Project description:Nonsense-mediated mRNA decay (NMD) monitors the quality of transcriptomes and degrades messenger RNAs containing splicing errors or premature stop codons. NMD thus dictates the severity and outcome of genetic disorders, gene edits and knockouts as well as the prevalence of neoantigens. Central to the NMD pathway are SMG-1, an ATM/ATR-like kinase, and its downstream target SMG-2/UPF1, a highly processive DNA/RNA helicase. Interestingly, many NMD factors acquired additional ‘moonlighting’ functions in the nucleus, including roles in DNA synthesis and DNA damage signalling. While having the same protein controlling RNA and DNA metabolism could be beneficial, it could also lead to signalling conflicts that jeopardize genome stability. Surprisingly little is known about the incidence and impact of such crosstalk in biology, neither in physiological nor in pathological scenarios. Here, via genetics screens and genome-wide analyses, we identified unforeseen crosstalk between RNA surveillance and DNA repair in living animals. Defects in RNA processing, due to viable THO complex or PNN-1 mutations, trigger SMG-1 activity, which causes a major shift in DNA repair and compromises genome stability in somatic tissues. Mechanistically, we find SMG-1 and SMG-2/UPF1, but not NMD per se, to suppress DNA repair by classical non-homologous end-joining while allowing mutagenic repair by single strand annealing. We postulate that aberrant RNA structures trigger crosstalk that re-directs DNA repair and genome evolution.
2022-08-12 | PXD022616 | Pride