Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1130837 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29675754.fastq.gz | Fastqsanger.gz | |||
| SRR29675755.fastq.gz | Fastqsanger.gz | |||
| SRR29675756.fastq.gz | Fastqsanger.gz | |||
| SRR29675757.fastq.gz | Fastqsanger.gz | |||
| SRR29675758.fastq.gz | Fastqsanger.gz |
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Project description:Nuclear metabolism and DNA damage response are intertwined processes, but the precise molecular connections remain elusive. Here, we delve into this crosstalk using as a model triple-negative breast cancer (TNBC), a subtype often prone to DNA damage accumulation. We reveal that the de novo purine synthesis enzyme Inosine monophosphate dehydrogenase 2 (IMPDH2) is enriched on chromatin in TNBC when compared to other subtypes. IMPDH2 chromatin localization is DNA damage dependent and IMPDH2 repression leads to DNA damage accumulation. On chromatin, IMPDH2 interacts and modulates Poly [ADP-ribose] polymerase 1 (PARP1) activity by controlling nuclear availability of nicotinamide adenine dinucleotide (NAD+) -a shared metabolic cofactor- to fine-tune the DNA damage response. However, when IMPDH2 is restricted to the nucleus, it depletes nuclear NAD+, leading to PARP1 cleavage and cell death. Our study identifies a non-canonical nuclear role for IMPDH2 that act as convergence point of nuclear metabolism and DNA damage response. # Contributed equally *Corresponding authors: sara.sdelci@crg.eu; marta.garciacao@crg.eu
2024-09-16 | GSE271269 | GEO
Project description:Recent studies have highlighted the critical role of metabolism in the response to DNA damage. However, the precise metabolic interactions that are set in motion to tune this fundamental process remain largely unknown. In this study, we investigated the role of nuclear metabolism in the DNA damage response using triple-negative breast cancer as a model. By comparing the chromatin-associated proteome of different breast cancer subtypes, we observed that the purine synthesis enzyme Inosine monophosphate dehydrogenase 2 (IMPDH2) is enriched in the chromatin of triple-negative breast cancer cells, which are often prone to DNA damage accumulation. Downregulation, depletion, or inhibition of IMPDH2 leads to accumulation of DNA damage. IMPDH2 chromatin localization is DNA damage dose dependent and happens at a late stage of the DNA damage repair. On chromatin, IMPDH2 interacts with PARP1. The enzymatic function of IMPDH2, which consumes NAD+, modulates PARP1 activity, thus mediating a pondered DNA damage response. However, forcing the nuclear localization of exogenous IMPDH2 provokes a dramatic NAD+ depletion that results in PARP1 cleavage and consequent cytoplasmic translocation, which mediates apoptosis. Our study identifies a moonlighting role for IMPDH2 in the control of nuclear ATP and NAD+ level, which fine-tune the activation of PARP1 and regulates the DNA damage response.
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Project description:Trabectedin is a DNA-damaging agent with a peculiar mechanism of action; it traps the DNA repair machinery leading to DNA single- and double-strand breaks, particularly in BRCA1/2-deficient tumors. We hypothesized that trabectedin-induced DNA damage might activate PARP1 (a DNA-repair machinery key player), and consequently, PARP1 inhibition would perpetuate trabectedin-induced DNA damage. In several tumor histotypes, we demonstrated a different degree of synergism between trabectedin and PARP1 inhibitors (PARP1-Is). Independent of BRCA1/2 status, PARP1 expression dictated the degree of synergism. Namely, silenced PARP1 reduced trabectedin-PARP1-Is synergism, whereas overexpressed PARP1 increased combination efficacy. High-PARP1 expression and specific gene signatures associated with DNA damage response and repair (DDR-R) were predictive of trabectedin+PARP1-I synergy. These findings pave the way for the clinical development of this novel combination therapy, as well as evaluation of PARP1 expression and DDR-R signatures in tumor samples as predictive biomarkers of response
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2010-05-27 | E-GEOD-19174 | biostudies-arrayexpress
Project description:Poly(ADP-ribose) polymerase 1 (PARP1) is a highly conserved nuclear protein in multicellular organisms that modulates chromatin opening, and by doing so, it plays a significant role in gene expression regulation during development and differentiation. Despite its significance, all reported Parp1 total knockout mice strains are viable and fertile with no developmental anomalies. It was previously believed that functional redundancy with other PARP family members explain such a controversy. PARP2 is the main candidate to fulfill PARP1 functions in Parp1 knockout mice. Indeed, Parp1 Parp2 double knockout mice are arrested early in development and unable to proceed through gastrulation. However, while PARP2 has similar catalytic domain to PARP1, it lacks other domains that play important regulatory roles, thus making the lack of developmental problems in Parp1 mice total knockouts highly unlikely. To address this question, we checked the best investigated and publicly available Parp1 knockout mice strain. We found that Parp1 is still expressed in these mice, based on the presence of its mRNA transcript. Contrary to prior assumptions, we identified persistent mRNA expression in knockout mice, albeit at reduced levels. Detailed transcript analysis revealed an alternatively spliced PARP1 variant lacking exon two with introduced artificial cassette. Subsequent protein analysis confirmed the existence of a truncated PARP1 protein in knockout mice. We established embryonic stem cell lines from knockout mice and revealed the presence of pADPr. The decreased level of pADPr was detected in knockout ES cells with Western Blotting analysis, but immunofluorescence staining didn’t detect any difference in distribution or level of pADPr in nuclei of knockout ES cells compared to control ones. Moreover, in double Parp1 Parg mutant ES cells the accumulation of pADPr greatly exceeded its amount in normal and even in hypomorph Parg mutant ES cells, suggesting the presence of functionally active PARP1. Therefore, our findings challenge the conventional understanding of PARP1 depletion effects.
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2016-10-12 | PXD003712 | Pride
Project description:BACKGROUND & AIMS: The immune system comprises an innate and an adaptive immune response to combat pathogenic agents. The human enteropathogen Salmonella enterica serovar Typhimurium invades the intestinal mucosa and triggers an early innate pro-inflammatory host gene response, which results in diarrheal disease. Several host factors are involved in the acute early response to Salmonella infection. Transcription factors and transcription co-regulators have an especially important function, because they are required for the expression and synthesis of pro-inflammatory cytokines, chemokines and adhesion molecules. A central transcription factor involved in inflammation is NF-κB, which requires the nuclear protein PARP1 as co-factor for the expression of some of its target genes. Here, we investigated the role of PARP1 during Salmonella infection using a mouse model for Salmonella-induced colitis. METHODS: To study enterocolitis by Salmonella Typhimurium, an established mouse model system, which relies on streptomycin-pretreatment prior to Salmonella infection, was employed. Histopathologic signs of inflammation and cecum colonization at various time-points after infection of wild type and PARP1 knockout mice were analyzed. PARP1 expression in the gut mucosa was studied by quantitative RT-PCR, Western blot and immunofluorescence. Gene expression profiles of infected and control infected mice in the wild type or PARP1 knockout background were obtained by whole mouse genome arrays and confirmed by quantitative RT-PCR.
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