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1.
bioRxiv ; 2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38895345

RESUMO

RNA polymerase (Pol) I, II, and III are most commonly described as having distinct roles in synthesizing ribosomal RNA (rRNA), messenger RNA (mRNA), and specific small noncoding (nc)RNAs, respectively. This delineation of transcriptional responsibilities is not definitive, however, as evidenced by instances of Pol II recruitment to genes conventionally transcribed by Pol III, including the co-transcription of RPPH1 - the catalytic RNA component of RNase P. A comprehensive understanding of the interplay between RNA polymerase complexes remains lacking, however, due to limited comparative analyses for all three enzymes. To address this gap, we applied a uniform framework for quantifying global Pol I, II, and III occupancies that integrates currently available human RNA polymerase ChIP-seq datasets. Occupancy maps are combined with a comprehensive multi-class promoter set that includes protein-coding genes, noncoding genes, and repetitive elements. While our genomic survey appropriately identifies recruitment of Pol I, II, and III to canonical target genes, we unexpectedly discover widespread recruitment of the Pol III machinery to promoters of specific protein-coding genes, supported by colocalization patterns observed for several Pol III-specific subunits. We show that Pol III-occupied Pol II promoters are enriched for small, nascent RNA reads terminating in a run of 4 Ts, a unique hallmark of Pol III transcription termination and evidence of active Pol III activity at these sites. Pol III disruption differentially modulates the expression of Pol III-occupied coding genes, which are functionally enriched for ribosomal proteins and genes broadly linked to unfavorable outcomes in cancer. Our map also identifies additional, currently unannotated genomic elements occupied by Pol III with clear signatures of nascent RNA species that are sensitive to disruption of La (SSB) - a Pol III-related RNA chaperone protein. These findings reshape our current understanding of the interplay between Pols II and III and identify potentially novel small ncRNAs with broad implications for gene regulatory paradigms and RNA biology.

2.
Anal Biochem ; 692: 115548, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38697593

RESUMO

Oviductus Ranae is the dried oviduct from Rana dybowskii, a forest frog species with medicinal, tonic, and cosmetic properties. Due to the high price and resource shortage, counterfeit varieties of Oviductus Ranae often appear in the market. However, traditional identification methods cannot accurately differentiate between Oviductus Ranae and its adulterants. In this study, a rapid molecular identification method has been established. The method involves extracting genomic DNA in just 30 s using filter paper purification, species-specific rapid polymerase chain reaction (PCR) amplification, and finally, fluorescence detection of the products. It can accurately identify Oviductus Ranae and its three common adulterants in about 30 min, making the process simple, fast, and highly specific.


Assuntos
Primers do DNA , Reação em Cadeia da Polimerase , Ranidae , Especificidade da Espécie , Animais , Ranidae/genética , Reação em Cadeia da Polimerase/métodos , Feminino , Oviductos/metabolismo , DNA/análise , DNA/genética , DNA/isolamento & purificação
3.
Cancers (Basel) ; 15(20)2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37894362

RESUMO

RNA polymerase III (Pol III) subunit RPC7α, which is encoded by POLR3G in humans, has been linked to both tumor growth and metastasis. Accordantly, high POLR3G expression is a negative prognostic factor in multiple cancer subtypes. To date, the mechanisms underlying POLR3G upregulation have remained poorly defined. We performed a large-scale genomic survey of mRNA and chromatin signatures to predict drivers of POLR3G expression in cancer. Our survey uncovers positive determinants of POLR3G expression, including a gene-internal super-enhancer bound with multiple transcription factors (TFs) that promote POLR3G expression, as well as negative determinants that include gene-internal DNA methylation, retinoic-acid induced differentiation, and MXD4-mediated disruption of POLR3G expression. We show that novel TFs identified in our survey, including ZNF131 and ZNF207, functionally enhance POLR3G expression, whereas MXD4 likely obstructs MYC-driven expression of POLR3G and other growth-related genes. Integration of chromatin architecture and gene regulatory signatures identifies additional factors, including histone demethylase KDM5B, as likely influencers of POLR3G gene activity. Taken together, our findings support a model in which POLR3G expression is determined with multiple factors and dynamic regulatory programs, expanding our understanding of the circuitry underlying POLR3G upregulation and downstream consequences in cancer.

4.
Arch Toxicol ; 96(7): 1951-1962, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35445828

RESUMO

N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) is a novel lipophilic metal chelator and antioxidant used in mercury poisoning. Recent studies have suggested that NBMI may also bind to other metals such as lead and iron. Since NBMI can enter the brain, we evaluated if NBMI removes excess iron from the iron-loaded brain and ameliorates iron-induced oxidative stress. First, NBMI exhibited preferential binding to ferrous (Fe2+) iron with a negligible binding affinity to ferric (Fe3+) iron, indicating a selective chelation of labile iron. Second, NBMI protected SH-SY5Y human neuroblastoma cells from the cytotoxic effects of high iron. NBMI also decreased cellular labile iron and lessened the production of iron-induced reactive oxygen species in these cells. Deferiprone (DFP), a commonly used oral iron chelator, failed to prevent iron-induced cytotoxicity or labile iron accumulation. Next, we validated the efficacy of NBMI in Hfe H67D mutant mice, a mouse model of brain iron accumulation (BIA). Oral gavage of NBMI for 6 weeks decreased iron accumulation in the brain as well as liver, whereas DFP showed iron chelation only in the liver, but not in the brain. Notably, depletion of brain copper and anemia were observed in BIA mice treated with DFP, but not with NBMI, suggesting a superior safety profile of NBMI over DFP for long-term use. Collectively, our study demonstrates that NBMI provides a neuroprotective effect against BIA and has therapeutic potential for neurodegenerative diseases associated with BIA.


Assuntos
Neuroblastoma , Animais , Humanos , Camundongos , Derivados de Benzeno , Encéfalo , Quelantes/farmacologia , Quelantes/uso terapêutico , Ferro/metabolismo , Neuroblastoma/metabolismo , Compostos de Sulfidrila
5.
Neurotoxicology ; 88: 88-101, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34748789

RESUMO

Iron is a key element for mitochondrial function and homeostasis, which is also crucial for maintaining the neuronal system, but too much iron promotes oxidative stress. A large body of evidence has indicated that abnormal iron accumulation in the brain is associated with various neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. However, it is still unclear how irregular iron status contributes to the development of neuronal disorders. Hence, the current review provides an update on the causal effects of iron overload in the development and progression of neurodegenerative diseases and discusses important roles of mitochondrial iron homeostasis in these disease conditions. Furthermore, this review discusses potential therapeutic targets for the treatments of iron overload-linked neurodegenerative diseases.


Assuntos
Ferro/metabolismo , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Humanos , Ferro/efeitos adversos , Doenças Neurodegenerativas/etiologia
6.
Front Mol Biosci ; 9: 1073795, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36710885

RESUMO

RNA polymerase III composition is shaped by the mutually exclusive incorporation of two paralogous subunits, RPC7α and RPC7ß, encoded by genes POLR3G and POLR3GL in vertebrates. The expression of POLR3G and POLR3GL is spatiotemporally regulated during development, and multiple reports point to RPC7α-enhanced Pol III activity patterns, indicating that Pol III identity may underly dynamic Pol III transcription patterns observed in higher eukaryotes. In cancer, upregulation of POLR3G, but not POLR3GL, is associated with poor survival outcomes among patients, suggesting differences between RPC7α and RPC7ß further influence disease progression and may translate into future biomarkers and therapeutic strategies. Here, we outline our current understanding of Pol III identity and transcription and reexamine the distinct protein characteristics of Pol III subunits RPC7α and RPC7ß. Drawing on both structural and genomic studies, we discuss differences between RPC7α and RPC7ß and the potential mechanisms by which Pol III identity may establish differential activities during development and disease.

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