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Nono stimulates the DNA damage response by mediating the induction of Gadd45b

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE250302 | GEO | 2024/06/04

REPOSITORIES: GEO

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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

Nono stimulates the DNA damage response by mediating the induction of Gadd45b

Project description:Nono stimulates the DNA damage response by mediating the induction of Gadd45b

| PRJNA1053326 | ENA

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

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

| PRJNA1053336 | ENA

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

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

| PRJNA1053329 | ENA

PARP activation regulates the RNA-binding protein NONO in the DNA damage response to DNA double-strand breaks.

Project description:After the generation of DNA double-strand breaks (DSBs), poly(ADP-ribose) polymerase-1 (PARP-1) is one of the first proteins to be recruited and activated through its binding to the free DNA ends. Upon activation, PARP-1 uses NAD+ to generate large amounts of poly(ADP-ribose) (PAR), which facilitates the recruitment of DNA repair factors. Here, we identify the RNA-binding protein NONO, a partner protein of SFPQ, as a novel PAR-binding protein. The protein motif being primarily responsible for PAR-binding is the RNA recognition motif 1 (RRM1), which is also crucial for RNA-binding, highlighting a competition between RNA and PAR as they share the same binding site. Strikingly, the in vivo recruitment of NONO to DNA damage sites completely depends on PAR, generated by activated PARP-1. Furthermore, we show that upon PAR-dependent recruitment, NONO stimulates nonhomologous end joining (NHEJ) and represses homologous recombination (HR) in vivo. Our results therefore place NONO after PARP activation in the context of DNA DSB repair pathway decision. Understanding the mechanism of action of proteins that act in the same pathway as PARP-1 is crucial to shed more light onto the effect of interference on PAR-mediated pathways with PARP inhibitors, which have already reached phase III clinical trials but are until date poorly understood.

| S-EPMC3488241 | biostudies-literature

DDX54 regulates transcriptome dynamics during DNA damage response

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-04-20 | GSE89369 | GEO

Active DNA demethylation promotes cell fate specification and the DNA damage response

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-12-01 | GSE210317 | GEO

NONO phase separation enhances DNA damage repair by accelerating nuclear EGFR-induced DNA-PK activation.

Project description:Radioresistance is one of the main causes of cancer treatment failure, which leads to relapse and inferior survival outcome of cancer patients. Liquid-liquid phase separation (LLPS) of proteins is known to be involved in various biological processes, whereas its role in the regulation of radiosensitivity remains largely unknown. In this study, we characterized NONO, an RNA/DNA binding protein with LLPS capacity, as an essential regulator of tumor radioresistance. In vitro assay showed that NONO involved in DNA repair via non-homologous end joining (NHEJ) manner. NONO knockout significantly reduced DNA damage repair and sensitized tumor cells to irradiation in vitro and in vivo. NONO overexpression was correlated with an inferior survival outcome in cancer patients. Mechanically, NONO was associated with nuclear EGFR (nEGFR). Both irradiation and EGF treatment induced nEGFR accumulation, thereby increased the association between NONO and nEGFR. However, NONO was not a substrate of EGFR kinase. Furthermore, NONO promoted DNA damage-induced DNA-PK phosphorylation at T2609 by enhancing the interaction between EGFR and DNA-PK. Importantly, NONO protein formed high concentration LLPS droplets in vitro, and recruited EGFR and DNA-PK. Disruption of NONO droplets with LLPS inhibitor significantly reduced the interaction between EGFR and DNA-PK, and suppressed DNA damage-induced phosphorylation of T2609-DNA-PK. Taken together, LLPS of NONO recruits nuclear EGFR and DNA-PK and enhances their interaction, further increases DNA damage-activated pT2609-DNA-PK and promotes NHEJ-mediated DNA repair, finally leads to tumor radioresistance. NONO phase separation-mediated radioresistance may serve as a novel molecular target to sensitize tumor cell to radiotherapy.

| S-EPMC8263645 | biostudies-literature

Nuclear phosphatidylinositol-5-phosphate regulates ING2 stability at discrete chromatin targets in response to DNA damage

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-12-31 | E-GEOD-47689 | biostudies-arrayexpress