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PBAF loss leads to DNA damage induced inflammatory signalling through defective G2/M checkpoint maintenance

ABSTRACT: PBRM1 deficiency in immortalised fibroblast cell line 1BR3-hTERT after ionising radiation treatment leads to more mitotic progression and more formation of micronucleated cells. Here, we performed total RNA-seq in 1BR3-hTERT parental line and PBRM1 knockout clones (PBRM1 KO3&KO5) under untreated (UT) or 48 hr post 6Gy irradiation condition. We found that the annotated DREAM complex target genes are less transcriptionally repressed in the 1BR3-hTERT PBRM1 knockout clones compared to the parental line after ionising radiation treatment. The results confirm our findings that PBRM1 deficiency leads to delayed p21 induction and delayed p130 hypo-phosphorylation, which leads to defective DREAM target gene repression and misregulated G2/M progression after ionising radiation treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183688 | GEO | 2022/09/07

REPOSITORIES: GEO

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PBAF loss leads to DNA damage induced inflammatory signalling through defective G2/M checkpoint maintenance

Project description:PBRM1 is a subunit of the PBAF (SWI/SNF) chromatin remodelling complex that is mutated in approximately 40% of clear cell renal cell carcinomas (ccRCC). PBRM1 loss has been implicated in the response to immune checkpoint inhibitor (ICI) therapy in ccRCC. However, it is unclear how PBRM1 influences this. DNA damage-induced inflammatory signalling is an important factor determining ICI therapy response. This response is kept in check by the G2/M checkpoint, which prevents progression through mitosis with unrepaired damage. Here, we show that PBRM1 is required for p53-dependent maintenance of the G2/M checkpoint. In its absence, p53-dependent transcriptional upregulation of p21 is delayed, leading to defective repression of DREAM complex targets and premature entry into mitosis. Consequently, DNA damage induced inflammatory signalling pathways are activated by cytosolic DNA. Notably, p53 is infrequently mutated in ccRCC, so PBRM1 mutational status is critical to G2/M checkpoint maintenance following DNA damage in this cancer. These findings have implications for ICI therapy responses in ccRCC.

2022-10-13 | PXD028336 | Pride

PITX1 suppresses TERT transcription

Project description:Using microcell-mediated chromosome transfer (MMCT) into the mouse melanoma cell line, B16F10, we have previously found that human chromosome 5 carries a gene, or genes, that can negatively regulate TERT expression. To identify the gene responsible for the regulation of TERT transcription, we performed cDNA microarray analysis using parental B16F10 cells, telomerase negative B16F10 microcell hybrids with a human chromosome 5 (B16F10MH5), and its revertant clones (MH5R) with reactivated telomerase. Here we report the identification of PITX1, whose restoration leads to the downregulation of mouse tert (mtert) transcription, as a TERT suppressor gene. Additionally, both human TERT (hTERT) and mouse TERT (mtert) promoter activity can be suppressed by PITX1. We showed that three and one binding sites, respectively, within the hTERT and mtert promoters that express a unique conserved region are responsible for the transcriptional activation of TERT. Furthermore, we showed that PITX1 binds to the TERT promoter both in vitro and in vivo. Thus, PITX1 suppresses TERT transcription through direct binding to the TERT promoter, which ultimately regulates telomerase activity. We transferred intact human chromosome 5 into mouse melanoma B16F10 cells by microcell fusion. The microcell hybrids (MH5) exhibited suppression of telomerase, we also obtained revertant clones (MH5R) in which telomerase is reactivated. To identify the differentially expressed genes on human chromosome 5, we performed expression microarray analysis using these two clones and parental B16F10 cells.

2010-09-10 | E-GEOD-23216 | biostudies-arrayexpress

Genetic and epigenetic changes in clonal descendants of irradiated human fibroblasts [strain 2]

Project description:To study delayed genetic and epigenetic radiation effects, which may trigger radiation-induced carcinogenesis, we have established single-cell clones from irradiated and non-irradiated primary human fibroblasts. Stable clones were endowed with the same karyotype in all analyzed metaphases after 20 population doublings (PDs), whereas unstable clones displayed mosaics of normal and abnormal karyotypes. To account for differences in radiation sensitivity, all experiments were performed with two different embryonic fibroblast strains. After a single dose of 2 Gray more than half of the irradiated clones exhibited radiation-induced genomic instability (RIGI). Methylation arrays identified several hundred differentially methylated genes and nine enriched pathways associated with in vitro ageing. Methylation changes in 259 genes and the MAP kinase signaling pathway were associated with delayed radiation effects (after 20 PDs). Collectively, our results suggest that both genetic and epigenetic changes occur in the progeny of exposed cells that were not damaged directly by irradiation, likely contributing to radiation-induced carcinogenesis.

2018-04-10 | GSE112873 | GEO

Genetic and epigenetic changes in clonal descendants of irradiated human fibroblasts [strain 1]

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Analysis of gene co-expression networks in skin cells exposed to different doses of ionising radiation at different time points

Project description:Most studies have analysed the effects of high dose radiation such as atomic bomb survivors in Japan, people exposed during the Chernobyl nuclear accident, patients undergoing radiation therapy, uranium miners, etc. However, it has been difficult to measure and assess the risk of cancer in people exposed to lower doses of ionising radiation, such as the people living at high altitudes, who are exposed to more natural background radiation from cosmic rays than people at sea level. We measured the genomic response to X-ray ionising radiation (10 cGy and 100 cGy) in a skin tissue model to compare the effects of low and high dose ionising radiation at different time points. The microarray data was then analysed using state-of-the art “upside-down pyramid” computational systems biology methods to identify genes contributing to the difference in the response to the different radiation doses.

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Radiation-Induced Genomic Instability in Caenorhabditis Elegans

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Dynamic regulation of the histone variant H1.0 contributes to intratumor epigenetic and functional heterogeneity [FAIRE-Seq]

Project description:Identification of nucleosome-free, active regulatory regions in in vitro generated CSCs and their parental hTERT-immortalized cell line.

2016-05-01 | GSE65519 | GEO

Analysis of gene co-expression networks in skin cells exposed to different doses of ionising radiation at different time points

2012-02-01 | E-GEOD-29344 | biostudies-arrayexpress

PITX1 suppresses TERT transcription

2010-09-10 | GSE23216 | GEO

long read RNA-seq from HFFc6 (ENCSR902GAF)

Project description:Clonal line 6 derived from hTert immortalized HFF parental line For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODE_Data_Use_Policy_for_External_Users_03-07-14.pdf

2020-01-06 | GSE143134 | GEO

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