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Cooperative targeting of PARP-1 domains to regulate metabolic and developmental genes.

ABSTRACT: PARP-1, also known as poly(ADP-ribose) polymerase 1, is a multifunctional nuclear enzyme that plays a critical role in transcriptional regulation through its three functional domains: the N-terminal DNA-binding domain (DBD) containing two zinc fingers for DNA binding and a third zinc finger for maintaining interdomain contacts, the auto modification domain (AD), and the C-terminal domain, which includes the protein-interacting WGR domain and the catalytic domain. Despite the critical role that PARP-1 plays in regulating gene expression, the mechanisms by which it is targeted to chromatin are not well understood. In this study, we aimed to understand the targeting of PARP-1 to chromatin using ChIP-seq of YFP-tagged deletional isoforms of PARP-1 (ZnI, ZnII, AD-WGR) and a construct that lacks only ZnI (ΔZnI). Our results indicate that other PARP-1 domains are sufficient to target PARP-1 to active genes in the absence of ZnI. Furthermore, we found that PARP-1 represses metabolic gene pathways and activates developmental gene pathways. The results of ChIP-seq analysis showed that PARP-1 and ΔZnI were preferentially bound to the gene bodies of PARP-1-regulated metabolic genes compared to developmental genes. PARP-1 domains (ZnI, ZnII and AD-WGR) also preferentially occupied the gene bodies of PARP-1-regulated metabolic genes, however, they were more enriched at the TSS of PARP-1-regulated developmental genes compared to metabolic genes. Thus, we propose that PARP-1 domains cooperatively target PARP-1 to PARP-1-regulated genes to coordinate metabolic and developmental gene expression programs.

SUBMITTER: Bamgbose G

PROVIDER: S-EPMC10281051 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Cooperative targeting of PARP-1 domains to regulate metabolic and developmental genes.

Bamgbose Gbolahan G Johnson Sarah S Tulin Alexei A

Frontiers in endocrinology 20230606

PARP-1, also known as poly(ADP-ribose) polymerase 1, is a multifunctional nuclear enzyme that plays a critical role in transcriptional regulation through its three functional domains: the N-terminal DNA-binding domain (DBD) containing two zinc fingers for DNA binding and a third zinc finger for maintaining interdomain contacts, the auto modification domain (AD), and the C-terminal domain, which includes the protein-interacting WGR domain and the catalytic domain. Despite the critical role that P ...[more]

PMID: 37347109

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Project description:BackgroundPancreatic ductal adenocarcinomas (PDA) activate a glutamine-dependent pathway of cytosolic nicotinamide adenine dinucleotide phosphate (NADPH) production to maintain redox homeostasis and support proliferation. Enzymes involved in this pathway (GLS1 (mitochondrial glutaminase 1), GOT1 (cytoplasmic glutamate oxaloacetate transaminase 1), and GOT2 (mitochondrial glutamate oxaloacetate transaminase 2)) are highly upregulated in PDA, and among these, inhibitors of GLS1 were recently deployed in clinical trials to target anabolic glutamine metabolism. However, single-agent inhibition of this pathway is cytostatic and unlikely to provide durable benefit in controlling advanced disease.ResultsHere, we report that reducing NADPH pools by genetically or pharmacologically (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) or CB-839) inhibiting glutamine metabolism in mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) PDA sensitizes cell lines and tumors to ß-lapachone (ß-lap, clinical form ARQ761). ß-Lap is an NADPH:quinone oxidoreductase (NQO1)-bioactivatable drug that leads to NADPH depletion through high levels of reactive oxygen species (ROS) from the futile redox cycling of the drug and subsequently nicotinamide adenine dinucleotide (NAD)+ depletion through poly(ADP ribose) polymerase (PARP) hyperactivation. NQO1 expression is highly activated by mutant KRAS signaling. As such, ß-lap treatment concurrent with inhibition of glutamine metabolism in mutant KRAS, NQO1 overexpressing PDA leads to massive redox imbalance, extensive DNA damage, rapid PARP-mediated NAD+ consumption, and PDA cell death-features not observed in NQO1-low, wild-type KRAS expressing cells.ConclusionsThis treatment strategy illustrates proof of principle that simultaneously decreasing glutamine metabolism-dependent tumor anti-oxidant defenses and inducing supra-physiological ROS formation are tumoricidal and that this rationally designed combination strategy lowers the required doses of both agents in vitro and in vivo. The non-overlapping specificities of GLS1 inhibitors and ß-lap for PDA tumors afford high tumor selectivity, while sparing normal tissue.

Dataset Information

Cooperative targeting of PARP-1 domains to regulate metabolic and developmental genes.

Publications

Cooperative targeting of PARP-1 domains to regulate metabolic and developmental genes.

Similar Datasets

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