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Effect of depletion of IMPDH1 and IMPDH2 on gene expression after DNA damage in HeLa cells

ABSTRACT: Effect of depletion of IMPDH1 and IMPDH2 on gene expression after DNA damage in HeLa cells

PROVIDER: PRJNA1104179 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28790348_1.fastq.gz	Fastqsanger.gz
	SRR28790348_2.fastq.gz	Fastqsanger.gz
	SRR28790349_1.fastq.gz	Fastqsanger.gz
	SRR28790349_2.fastq.gz	Fastqsanger.gz
	SRR28790350_1.fastq.gz	Fastqsanger.gz

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Effect of depletion of IMPDH1 and IMPDH2 on gene expression after DNA damage in HeLa cells

Project description:Guanosine nucleotide (GTP) serves as a pivotal purine nucleoside triphosphate, essential for DNA and RNA structure and function. Additionally, it acts as an activator for the guanine-binding protein family (G protein), participating in crucial cellular processes such as cytoskeleton rearrangement, membrane transport, protein synthesis, and signal transduction. IMPDH1 and IMPDH2 are key enzymes in the de novo synthesis of guanine nucleotides. Our research shows that they exhibit differential activities under DNA damage conditions. Specifically, IMPDH1 predominantly maintains enzymatic activity during DNA damage, facilitating GTP synthesis and cell survival. Our data indicate that following DNA damage, IMPDH1 and IMPDH2 affect distinct pathways in cells, with IMPDH1 potentially promoting the expression of homologous recombination repair proteins.

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Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

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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Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

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

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Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

Project description:Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

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Project description:Metabolic dysregulation is one of the most common causes of pediatric neurodegenerative disorders. However, how the disruption of ubiquitous and essential metabolic pathways predominantly affect neural tissue remains unclear. Here we use a mouse model of AMPD2 deficiency to study cellular and molecular mechanisms that lead to selective neuronal vulnerability to purine metabolism imbalance. We show that AMPD deficiency in mice primarily leads to hippocampal dentate gyrus degeneration despite causing a generalized reduction of brain GTP levels. Remarkably, we uncover that neurodegeneration resistant regions of the hippocampus accumulate micron sized filaments of IMPDH2, the rate limiting enzyme in GTP synthesis. In contrast, IMPDH2 filaments are barely detectable in the dentate gyrus, which show a progressively neuroinflammation and neurodegeneration. Furthermore, using a human AMPD2 neural cell culture model, we show that blocking IMPDH2 polymerization with a dominant negative IMPDH2 variant impairs AMPD2 deficient neural progenitor growth. Together, our findings suggest that IMPDH2 polymerization prevents detrimental GTP deprivation caused by AMPD2 deficiency, providing resistance to neurodegeneration. This data opens the possibility of exploring the involvement of IMPDH2 assembly as a therapeutic intervention for neurodegeneration.

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