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Cytoplasmic NAD+ Synthesis and Ribosomal Protein Mono(ADP-Ribosyl)ation Maintain Proteostasis in Ovarian Cancer

ABSTRACT: Global protein synthesis is upregulated in cancers, and thus cancer cells are prone to errors in translation, which may lead to protein misfolding and proteotoxic stress. The pathways that maintain protein homeostasis support the transformation and growth of cancer cells. Here, we show that the cytosolic NAD+ synthesis pathway (controlled by NMNAT-2) plays an essential role in ovarian cancer by maintaining protein homeostasis by regulating the activity of PARP-16, that MARylates the ribosomal proteins. Using polysome-RNA Seq analysis, we found that inhibiting ribosomal protein MARylation by knocking down NMNAT-2 or PARP-16 leads to increased association of specific mRNAs with polysomes and enhanced translation of a set of mRNAs that contain specific secondary structures in their 3’UTRs, which leads to protein aggregation. Collectively, our study demonstrates that NMNAT-2 regulates PARP-16 activity and ribosomal protein MARylation, which control protein homeostasis by fine-tuning the levels of protein synthesis in ovarian cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146458 | GEO | 2021/07/26

REPOSITORIES: GEO

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Project description:Many of the long-term effects of cocaine on the brain's reward circuitry have been shown to be mediated by alterations in gene expression. Several chromatin modifications, including histone acetylation and methylation, have been implicated in this regulation, but the effect of other histone modifications remains poorly understood. Poly(ADP-ribose) polymerase-1 (PARP-1), a ubiquitous and abundant nuclear protein, catalyzes the synthesis of a negatively charged polymer called poly(ADP-ribose) or PAR on histones and other substrate proteins and forms transcriptional regulatory complexes with several other chromatin proteins. Here, we identify an essential role for PARP-1 in cocaine-induced molecular, neural, and behavioral plasticity. Repeated cocaine administration, including self-administration, increased global levels of PARP-1 and its mark PAR in mouse nucleus accumbens (NAc), a key brain reward region. Using PARP-1 inhibitors and viral-mediated gene transfer, we established that PARP-1induction in NAc mediates enhanced behavioral responses to cocaine, including increased self-administration of the drug. Using chromatin immunoprecipitation sequencing, we demonstrated a global, genome-wide enrichment of PARP-1 in NAc of cocaine-exposed mice and identified several PARP-1 target genes that could contribute to the lasting effects of cocaine. Specifically, we identified sidekick-1-important for synaptic connections during development-as a critical PARP-1 target gene involved in cocaine's behavioral effects as well as in its ability to induce dendritic spines on NAc neurons. These findings establish the involvement of PARP-1 and PARylation in the long-term actions of cocaine. c57bl/6 mice were given IP injections of chronic cocaine 20mg/kg once per day for 7 days and sacrificed 30 minutes after the final dose of cocaine. Control animals were given saline for 7 days and sacrificed 30 minutes after the final dose of saline. Nucleus accumbens (NAc) tissue was collected and then PARP-1 ChIP-seq was performed. Three sequencing replicates were performed on each group.

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Cytoplasmic NAD+ Synthesis and Ribosomal Protein Mono(ADP-Ribosyl)ation Maintain Proteostasis in Ovarian Cancer

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