NAD+ (nicotinamide adenine dinucleotide in its oxidized state) is an essential molecule for a variety of physiological processes. It synthesized distinct subcellular compartments by three different synthases (NMNAT-1, -2, and -3). We found that compartmentalized synthesis NMNATs integrates glucose metabolism adipogenic transcription during adipocyte differentiation. Adipogenic signaling rapidly induces cytoplasmic NMNAT-2, which competes with nuclear NMNAT-1 the common substrate,...

Some polypeptide N-acetyl-galactosaminyltransferases (GALNTs) are associated with cancer, but their function in organ-specific metastasis remains unclear. Here, we report that GALNT14 promotes breast cancer to the lung by enhancing initiation of metastatic colonies as well subsequent growth into overt metastases. Our results suggest augments self-renewal properties cells (BCCs). Furthermore, overcomes inhibitory effect lung-derived bone morphogenetic proteins (BMPs) on and therefore...

PARP-7 (TiPARP) is a mono(ADP-ribosyl) transferase whose protein substrates and biological activities are poorly understood. We observed that

Abstract STAT1α is a key transcription factor driving pro-inflammatory responses in macrophages. We found that the interferon gamma (IFNγ)-regulated transcriptional program macrophages controlled by ADP-ribosylation (ADPRylation) of STAT1α, post-translational modification resulting site-specific covalent attachment ADP-ribose moieties. PARP-1, major nuclear poly(ADP-ribose) polymerase (PARP), supports IFNγ-stimulated enhancer formation regulating genome-wide binding and IFNγ-dependent...

Mono(ADP-ribosyl)ation (MARylation) is emerging as a critical regulator of ribosome function and translation. Herein, we demonstrate that RACK1, an integral component the ribosome, MARylated by mono(ADP-ribosyl) transferase (MART) PARP14 in ovarian cancer cells. MARylation RACK1 required for stress granule formation promotes colocalization granules with G3BP1, eIF3η, 40S ribosomal proteins. In parallel, observed reduced translation subset mRNAs, including those encoding key regulators (e.g.,...

Recent studies have demonstrated that a subset of long noncoding RNAs (lncRNAs) produce functional polypeptides and proteins. In this study, we discovered 132 amino acid protein in human breast cancer cells named XCP (X-linked Cancer-associated Polypeptide), which is encoded by lncRNA1456 (a.k.a. RHOXF1P3), transcript previously thought to be noncoding. pancreas- testis-specific RNA whose gene located on chromosome X. We found the expression are highly upregulated luminal A, B, HER2...

We have identified PARP7, an NAD+-dependent mono(ADP-ribosyl) transferase, as a key regulator of the C/EBPβ-dependent proadipogenic transcription program. Moreover, PARP7 is required for efficient adipogenesis and downstream biological functions, including involution lactating mammary gland. serves coregulator C/EBPβ, depletion causes dramatic reduction in C/EBPβ binding across genome. functions sensor nuclear NAD+ levels to control gene expression. At relatively high concentrations...

With half a million babies born preterm each year in the USA and about 15 worldwide, birth (PTB) remains global health issue. Preterm is primary cause of infant morbidity mortality can impact lives long past infancy. The fact that there are numerous, many currently unidentified, etiologies PTB has hindered development tools for risk evaluation preventative therapies. Infection estimated to be involved nearly 40% PTBs known etiology; therefore, understanding how infection-mediated...

Abstract Histone acetylation plays a pivotal role in transcriptional regulation and ATP-dependent nucleosome remodeling activity is required for optimal transcription from chromatin. While these two activities have been well characterized, how they are coordinated remains to be determined. We discovered histone H2A Drosophila nuclear extracts. This was column purified demonstrated composed of the enzymatic CREB-binding protein (CBP) SMARCAD1, which belongs Etl1 subfamily Snf2 family...

Abstract Inhibitors of nuclear PARP enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to inhibitors (PARPi). We sought identify an biomarker that could predict responses both conventional chemotherapy and PARPi cancers. focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by...

Abstract Cervical cancer continues to be a significant cause of cancer-related deaths in women. The most common treatment for cervical involves the use drug cisplatin conjunction with other therapeutics. However, development resistance patients can hinder efficacy these treatments, so alternatives are needed. In this study, we found that PARP inhibitors (PARPi) could attenuate growth cells representing adenocarcinoma and squamous cell carcinoma. Moreover, combination PARPi increased...

Abstract Mono(ADP-ribosyl)ation (MARylation) is emerging as a critical regulator of ribosome function and translation. Herein, we demonstrate that RACK1, an integral component the ribosome, MARylated on three acidic residues by mono(ADP-ribosyl) transferase (MART) PARP14 in ovarian cancer cells. MARylation RACK1 required for stress granule formation promotes colocalization granules with G3BP1, eIF3η, 40S ribosomal proteins. In parallel, observed reduced translation subset mRNAs, including...

The ovarian hormones estrogen and progesterone orchestrate the transcriptional programs required to direct functions of uterus for initiation maintenance pregnancy. Estrogen, acting via receptor alpha, regulates gene expression by activating repressing distinct genes involved in signaling pathways that regulate cellular physiological responses including cell division, water influx, immune recruitment. Historically, these have been postulated reflect a biphasic response. In this study, we...

Abstract Estradiol (E2) and relaxin (Rln) are steroid polypeptide hormones, respectively, with important roles in the female reproductive tract, including myometrium. Some actions of Rln, which mediated by its membrane receptor RXFP1, require or augmented E2 signaling through cognate nuclear receptor, estrogen alpha (ERα). In contrast, other Rln act opposition to effects E2. Here we explored molecular genomic mechanisms that underlie functional interplay between We used both ovariectomized...

Abstract Signal-induced transcriptional programs regulate critical biological processes through the precise spatiotemporal activation of Immediate Early Genes (IEGs); however, mechanisms transcription induction remain poorly understood. By combining an acute depletion system with high resolution genomics approaches to interrogate synchronized, temporal transcription, we reveal that KAP1/TRIM28 is a first responder fulfills and heightened demand IEGs. Unexpectedly, KAP1 loss triggers increase...

Estradiol (E2) and relaxin (Rln) are steroid polypeptide hormones, respectively, with important roles in the female reproductive tract, including myometrium. Some actions of Rln, which mediated by its membrane receptor RXFP1, require or augmented E2 signaling through cognate nuclear receptor, estrogen alpha (ERα). In contrast, other Rln act opposition to effects E2. Here we explored molecular genomic mechanisms that underlie functional interplay between We used both ovariectomized mice...

Abstract Long noncoding RNAs have been implicated in many of the hallmarks cancer. Herein, we found that expression lncRNA152 (lnc152; a.k.a. DRAIC), which annotated previously, is highly upregulated luminal breast cancer (LBC) and downregulated triple-negative (TNBC). Knockdown lnc152 promotes cell migration invasion LBC lines. In contrast, ectopic inhibits growth, migration, invasion, angiogenesis TNBC mice, inhibited growth xenografts, as well metastasis cells an intracardiac injection...

Abstract Breast cancer is the most common diagnosed in women. At time of diagnosis, approximately 70% breast cancers express Estrogen Receptor alpha (ERα), a key signature luminal subtype tumors. Equally important these cases expression FoxA1, subtype-specific transcription factor (TF) essential for ERα-mediated cell proliferation. FoxA1 pioneer TF that assists ERα with assembly enhancers and estrogen (E2)-regulated target genes. Together, FoxA1-ERα axis major driver growth. Our recently...

Abstract Signal-induced transcriptional programs regulate critical biological processes through the precise spatiotemporal activation of Immediate Early Genes (IEGs); however, mechanisms transcription induction remain poorly understood. By combining an acute depletion system with several genomics approaches to interrogate synchronized, temporal transcription, we reveal that KAP1/TRIM28 is a first responder fulfills and heightened demand IEGs. Acute KAP1 loss triggers increase in RNA...

Abstract Disclosure: J. Zhu: None. R. Gupte: T.S. Nandu: W.L. Kraus: D. Huang: Adipose tissue macrophages play a significant role in maintaining adipose homeostasis, as well promoting chronic low-grade inflammation during the development of obesity and metabolic dysfunction. However, crosstalk between adipocytes, especially how affect adipogenesis obese tissue, are still poorly understood. We have investigated function PARP1 control by using an adipocyte precursor-specific Parp1 knockout...

Abstract Disclosure: H. Kim: None. T.S. Nandu: W.L. Kraus: Estrogens are steroid hormones that play a key role in wide range of physiological and pathological processes. The predominant nuclear receptor for estrogens, estrogen receptor-alpha (ERɑ), functions primarily as transcription factor (TF) through ligand-dependent activation by 17β-estradiol (E2), the major naturally-occurring estrogen. levels E2 regulated production, sequestration, degradation, which can limit amount bioavailable E2....

Abstract Disclosure: H. Kim: None. T.S. Nandu: W.L. Kraus: Estrogens are steroid hormones that play a key role in wide range of physiological and pathological processes. The predominant nuclear receptor for estrogens, estrogen receptor-alpha (ERɑ), functions primarily as transcription factor (TF) through ligand-dependent activation by 17β-estradiol (E2), the major naturally-occurring estrogen. levels E2 regulated production, sequestration, degradation, which can limit amount bioavailable E2....