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NEAT1 promotes genome stability via m6A methylation-dependent regulation of CHD4 [Cut&Run]

ABSTRACT: Long non-coding (lnc)RNA emerge as regulators of genome stability. The abundant nuclear enriched transcript 1 (NEAT1) locus encodes two lncRNA isoforms that modulate gene expression, growth and proliferation in mammals. Interestingly, NEAT1 transcripts are overexpressed in many tumours and induced by DNA damage, suggesting a genome-protective function. However, the precise role of NEAT1 in the DNA damage response (DDR) is unclear. Here, we investigate the expression, modification levels, localization and structure of NEAT1 in response to DNA double-strand breaks (DSBs) induced by the topoisomerase-II inhibitor etoposide or the locus-specific endonuclease AsiSI. We find that induction of DSBs increases both the levels and N6-methyladenosine (m6A) marks on NEAT1, which promotes alterations in NEAT1 secondary structure and accumulation of hyper-methylated NEAT1 at a subset of promoter-associated DSBs to facilitate efficient DSB signalling. The depletion of NEAT1, in turn, delays the response to DSBs and triggers elevated DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves spreading of the chromodomain helicase DNA binding protein 4 (CHD4) upon release from NEAT1. Together, we describe a novel RNA-dependent DDR pathway that couples NEAT1 to the recognition and repair of DSBs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255342 | GEO | 2024/09/16

REPOSITORIES: GEO

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NEAT1 promotes genome stability via m6A methylation-dependent regulation of CHD4

Project description:Long non-coding (lnc)RNA emerge as regulators of genome stability. The nuclear enriched abundant transcript 1 (NEAT1) locus encodes two lncRNA isoforms that modulate gene expression, growth and proliferation in mammals. Interestingly, NEAT1 transcripts are overexpressed in many tumours and induced by DNA damage, suggesting a genome-protective function. However, the precise role of NEAT1 in the DNA damage response (DDR) is unclear. Here, we investigate the expression, modification levels, localization and structure of NEAT1 in response to DNA double-strand breaks (DSBs) induced by the topoisomerase-II inhibitor etoposide or the locus-specific endonuclease AsiSI. We find that induction of DSBs increases both the levels and N6-methyladenosine (m6A) marks on NEAT1, which promotes alterations in NEAT1 secondary structure and accumulation of hyper-methylated NEAT1 at a subset of promoter-associated DSBs to facilitate efficient DSB signalling. The depletion of NEAT1, in turn, delays the response to DSBs and triggers elevated DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves spreading of the chromodomain helicase DNA binding protein 4 (CHD4) upon release from NEAT1. Together, we describe a novel RNA-dependent DDR pathway that couples NEAT1 to the recognition and repair of DSBs.

2024-09-17 | GSE256233 | GEO

NEAT1 promotes genome stability via m6A methylation-dependent regulation of CHD4 [CHART-seq]

Project description:Long non-coding (lnc)RNA emerge as regulators of genome stability. The abundant nuclear enriched transcript 1 (NEAT1) locus encodes two lncRNA isoforms that modulate gene expression, growth and proliferation in mammals. Interestingly, NEAT1 transcripts are overexpressed in many tumours and induced by DNA damage, suggesting a genome-protective function. However, the precise role of NEAT1 in the DNA damage response (DDR) is unclear. Here, we investigate the expression, modification levels, localization and structure of NEAT1 in response to DNA double-strand breaks (DSBs) induced by the topoisomerase-II inhibitor etoposide or the locus-specific endonuclease AsiSI. We find that induction of DSBs increases both the levels and N6-methyladenosine (m6A) marks on NEAT1, which promotes alterations in NEAT1 secondary structure and accumulation of hyper-methylated NEAT1 at a subset of promoter-associated DSBs to facilitate efficient DSB signalling. The depletion of NEAT1, in turn, delays the response to DSBs and triggers elevated DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves spreading of the chromodomain helicase DNA binding protein 4 (CHD4) upon release from NEAT1. Together, we describe a novel RNA-dependent DDR pathway that couples NEAT1 to the recognition and repair of DSBs.

2024-09-16 | GSE255340 | GEO

NEAT1 promotes genome stability via m6A methylation-dependent regulation of CHD4 [seCLIP-seq]

2024-09-16 | GSE255341 | GEO

NEAT1 promotes genome stability via m6A methylation-dependent regulation of CHD4

Project description:Long non-coding (lnc)RNA emerge as regulators of genome stability. The nuclear enriched abundant transcript 1 (NEAT1) is overexpressed in many tumours and responsive to genotoxic stress. However, the mechanism that links NEAT1 to DNA damage response (DDR) is unclear. Here, we investigate the expression, modification levels, localization and structure of NEAT1 in response to DNA double-strand breaks (DSBs). DNA damage increases the levels and N6-methyladenosine (m6A) marks on NEAT1, which promotes alterations in NEAT1 structure, accumulation of hyper-methylated NEAT1 at promoter-associated DSBs and DSB foci formation. The depletion of NEAT1 delays DSB signalling and elevates DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves the release of the chromodomain helicase DNA binding protein 4 (CHD4) from NEAT1 to fine-tune histone deacetylation, which links NEAT1 to DDR.

2024-09-16 | GSE273351 | GEO

Non redundant functions of ATM and DNAPKcs in response to clean DNA Double Strand Breaks.

Project description:DNA Double Strand Breaks (DSBs) are harmful lesions that require rapid detection and repair in order to avoid toxic genomic rearrangements. DSBs elicit the so called DNA Damage Response (DDR), largely relying on ataxia telangiectasia mutated (ATM) and DNA Protein Kinase (DNAPK), two members of the PI3K-like kinase family, whose respective functions during the sequential steps of the DDR remains controversial. Using the DIvA cell line, expressing the AsiSI restriction enzyme, we have investigated the role of ATM and DNAPK in several aspects of the DDR upon induction of multiple clean DSBs throughout the human genome. High resolution mapping revealed that they are activated and spread in cis on a confined region surrounding all DSBs, independently of the pathway used for repair. However, a thorough analysis of repair kinetics, H2AX domain establishment and H2AX foci structure and dynamics revealed non overlapping functions for the two kinases once recruited at DSBs. Our results suggest that ATM is not solely acting on chromatin marks but also on chromatin organisation in order to ensure repair accuracy and survival.

2015-09-30 | E-MTAB-2992 | biostudies-arrayexpress

Nono stimulates the DNA damage response by mediating the induction of Gadd45b [RNA-seq]

Project description:RNA-binding proteins (RBPs) are frequently deregulated in cancer and emerge as effectors of the DNA damage response (DDR). The non-POU domain-containing octamer-binding protein NONO/p54nrb is a multi-functional RBP that modulates the production and processing of mRNA in unperturbed cells, but also promotes the repair of DNA double-strand breaks (DSBs). Here, we investigate the impact of Nono deletion in the murine cell-based lung cancer model KP (KRasG12D, Trp53-/-). We show that the deletion of Nono impairs the response to DSBs induced by the topoisomerase-II inhibitor etoposide. Nono-deficient KP (KPN) cells display prolonged activation of DSB signaling and an increased amount of DSBs. The defects in the DDR are accompanied with reduced RNAPII promoter occupancy, elevated levels of DNA-RNA-hybrids (R-loops), and attenuated induction of the DDR factor growth arrest and DNA damage inducible beta (Gadd45b). Our data suggest a Nono-mediated, genome-protective crosstalk of the DDR with the RNA metabolism. Our data characterise Gadd45b as putative Nono-dependent effector of the DDR and suggest that Nono mediates a genome-protective crosstalk of the DDR with the RNA metabolism via induction of Gadd45b.

2024-06-04 | GSE250301 | GEO

Nono stimulates the DNA damage response by mediating the induction of Gadd45b [CUT&Run]

2024-06-04 | GSE250297 | GEO

Tyrosine kinase c-Abl couples RNA polymerase II transcription to an RNA-dependent DNA damage response

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

Cell cycle-dependent resolution of DNA double-strand breaks repair

Project description:Damage to genomic DNA, especially as DNA double strand breaks (DSB), elicits prompt activation of DNA damage response (DDR) which arrest cell-cycle either G1/S or G2/M to avoid entering S and M phase with DNA damage. In mammalian organs cells are in both proliferating and quiescent states. Quiescent cells are already arrested in G0, therefore there may be fundamental difference in DDR between proliferating and quiescent cells. To address these differences we studied recruitment of DSB repair factors and resolution of DNA lesions induced at site-specific DSBs occurring at different cell cycle phases, i.e. in asynchronously proliferating, G0, and G1 arrested cells. Strikingly, DSBs occurring in G0 quiescent cells are irreparable with a sustained activation of p53-pathway. Conversely, reentry of G0-damaged cells into cell cycle progression, show a delayed clearance of recruited DNA repair factors bound at DSBs, indicating an inefficient repair when compared to DSBs induced in asynchronously proliferating or G1 cells. Moreover, we found that initial recognition of DSBs and assembly of DSB factors is largely similar at different cell cycle phases. Our study thereby demonstrates the crucial role of cell cycle phases in repair and resolution of DSBs.

2015-12-30 | GSE71447 | GEO

DRIP-seq files for: DDX17 is required for efficient DSB repair at DNA:RNA hybrid deficient loci

Project description:Determining the role of DDX17 in the formation of DNA:RNA-hybrids around active DNA double-strand breaks (DSBs) using DRIP-seq in the damaged induced via AsiSI (DIvA) cell system that induced DSBs at known genomic loci in response to hydroxytamoxifen (OHT) treatment via and AsiSI enzyme fused to an oestrogen receptor. Sequencing was done using either control or DDX17 siRNA, and mock or 4 hours 300nM OHT treatment. Paired-end 150 cycles was completed on an Illumina NextSeq 500 and library prep was completed using the NEB NEBNext Ultra II library prep kit.

2022-11-08 | E-MTAB-10814 | biostudies-arrayexpress

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