Pan-cancer analysis reveals that CTC1-STN1-TEN1 (CST) complex may have a key position in oncology.

Telomere dysfunction is one of the hallmarks of cancer, which puts telomere-associated genes in a prominent position in oncology. The CTC1-STN1-TEN1 (CST) complex is vital for telomere maintenance and participates in several steps of DNA metabolism, such as repair and replication, essential functions for malignant cells. Despite this, little is known about these genes in cancer biology. Here, using bioinformatics tools, we performed a study in 33 cancer types and over 10,000 TCGA samples analyzing the role of the CST complex in cancer. We obtained the somatic landscape and gene expression patterns of each of the subunits of the complex studied. Furthermore, we show that CST is important for genetic stability and nucleic acid metabolism in cancer. We identify possible interactors, transcription factors, and microRNAs associated with CST and two drugs that may disrupt their pathways. In addition, we show that CST gene expression is associated with cancer survival and recurrence in several tumor types. Finally, we show negative and positive correlations between immune checkpoint genes and CST in different types of cancer. With this work, we corroborate the importance of these genes in cancer biology and open perspectives for their use in other works in the field.

Current Progress and Perspectives on Using Gold Compounds for the Modulation of Tumor Cell Metabolism.

Altered cellular metabolism, which is essential for the growth and survival of tumor cells in a specific microenvironment, is one of the hallmarks of cancer. Among the most significant changes in the metabolic pattern of tumor cells is the shift from oxidative phosphorylation to aerobic glycolysis for glucose utilization. Tumor cells also exhibit changes in patterns of protein and nucleic acid metabolism. Recently, gold compounds have been shown to target several metabolic pathways and a number of metabolites in tumor cells. In this review, we summarize how gold compounds modulate glucose, protein, and nucleic acid metabolism in tumor cells, resulting in anti-tumor effects. We also discuss the rationale underlying the anti-tumor effects of these gold compounds and highlight how to effectively utilize against various types of tumors.

History of DNA Helicases.

Since the discovery of the DNA double helix, there has been a fascination in understanding the molecular mechanisms and cellular processes that account for: (i) the transmission of genetic information from one generation to the next and (ii) the remarkable stability of the genome. Nucleic acid biologists have endeavored to unravel the mysteries of DNA not only to understand the processes of DNA replication, repair, recombination, and transcription but to also characterize the underlying basis of genetic diseases characterized by chromosomal instability. Perhaps unexpectedly at first, DNA helicases have arisen as a key class of enzymes to study in this latter capacity. From the first discovery of ATP-dependent DNA unwinding enzymes in the mid 1970's to the burgeoning of helicase-dependent pathways found to be prevalent in all kingdoms of life, the story of scientific discovery in helicase research is rich and informative. Over four decades after their discovery, we take this opportunity to provide a history of DNA helicases. No doubt, many chapters are left to be written. Nonetheless, at this juncture we are privileged to share our perspective on the DNA helicase field - where it has been, its current state, and where it is headed.

Transcriptome Analysis of FEN1 Knockdown HEK293T Cell Strain Reveals Alteration in Nucleic Acid Metabolism, Virus Infection, Cell Morphogenesis and Cancer Development.

AIM AND OBJECTIVE: Flap endonuclease-1 (FEN1) plays a central role in DNA replication and DNA damage repair process. In mammals, FEN1 functional sites variation is related to cancer and chronic inflammation, and supports the role of FEN1 as a tumor suppressor. However, FEN1 is overexpressed in multiple types of cancer cells and is associated with drug resistance, supporting its role as an oncogene. Hence, it is vital to explore the multi-functions of FEN1 in normal cell metabolic process. This study was undertaken to examine how the gene expression profile changes when FEN1 is downregulated in 293T cells. MATERIALS AND METHODS: Using the RNA sequencing and real-time PCR approaches, the transcript expression profile of FEN1 knockdown HEK293T cells have been detected for the next step evaluation, analyzation, and validation. RESULTS: Our results confirmed that FEN1 is important for cell viability. We showed that when FEN1 downregulation led to the interruption of nucleic acids related metabolisms, cell cycle related metabolisms are significantly interrupted. FEN1 may also participate in non-coding RNA processing, ribosome RNA processing, transfer RNA processing, ribosome biogenesis, virus infection and cell morphogenesis. CONCLUSION: These findings provide insight into how FEN1 nuclease might regulate a wide variety of biological processes, and laid the foundation for understanding the role of other RAD2 family nucleases in cell growth and metabolism.

Role of DHH superfamily proteins in nucleic acids metabolism and stress tolerance in prokaryotes and eukaryotes.

DHH superfamily proteins play pivotal roles in various cellular processes like replication, recombination, repair and nucleic acids metabolism. These proteins are important for homeostasis maintenance and stress tolerance in prokaryotes and eukaryotes. The prominent members of DHH superfamily include single-strand specific exonuclease RecJ, nanoRNases, polyphosphatase PPX1, pyrophosphatase, prune phosphodiesterase and cell cycle protein Cdc45. The mutations of genes coding for DHH superfamily proteins lead to severe growth defects and in some cases, may be lethal. The members of superfamily have a wide substrate spectrum. The spectrum of substrate for DHH superfamily members ranges from smaller molecules like pyrophosphate and cyclic nucleotides to longer single-stranded DNA molecule. Several genetic, structural and biochemical studies have provided interesting insights about roles of DHH superfamily members. However, there are still various unexplored members in both prokaryotes and eukaryotes. Many aspects of this superfamily associated with homeostasis maintenance and stress tolerance are still not clearly understood. A comprehensive understanding is pre-requisite to decipher the physiological significance of members of DHH superfamily. This article provides the current understanding of DHH superfamily members and their significance in nucleic acids metabolism and stress tolerance across diverse forms of life.

3.3-Å resolution cryo-EM structure of human ribonucleotide reductase with substrate and allosteric regulators bound.

Ribonucleotide reductases (RNRs) convert ribonucleotides into deoxyribonucleotides, a reaction essential for DNA replication and repair. Human RNR requires two subunits for activity, the α subunit contains the active site, and the ß subunit houses the radical cofactor. Here, we present a 3.3-Å resolution structure by cryo-electron microscopy (EM) of a dATP-inhibited state of human RNR. This structure, which was determined in the presence of substrate CDP and allosteric regulators ATP and dATP, has three α2 units arranged in an α6 ring. At near-atomic resolution, these data provide insight into the molecular basis for CDP recognition by allosteric specificity effectors dATP/ATP. Additionally, we present lower-resolution EM structures of human α6 in the presence of both the anticancer drug clofarabine triphosphate and ß2. Together, these structures support a model for RNR inhibition in which ß2 is excluded from binding in a radical transfer competent position when α exists as a stable hexamer.

Impact of hepatitis B virus infection on hepatic metabolic signaling pathway.

A growing body of epidemiologic research has demonstrated that metabolic derangement exists in patients with hepatitis B virus (HBV) infection, indicating that there are clinical associations between HBV infection and host metabolism. In order to understand the complex interplay between HBV and hepatic metabolism in greater depth, we systematically reviewed these alterations in different metabolic signaling pathways due to HBV infection. HBV infection interfered with most aspects of hepatic metabolic responses, including glucose, lipid, nucleic acid, bile acid and vitamin metabolism. Glucose and lipid metabolism is a particular focus due to the significant promotion of gluconeogenesis, glucose aerobic oxidation, the pentose phosphate pathway, fatty acid synthesis or oxidation, phospholipid and cholesterol biosynthesis affected by HBV. These altered metabolic pathways are involved in the pathological process of not only hepatitis B, but also metabolic disorders, increasing the occurrence of complications, such as hepatocellular carcinoma and liver steatosis. Thus, a clearer understanding of the hepatic metabolic pathways affected by HBV and its pathogenesis is necessary to develop more novel therapeutic strategies targeting viral eradication.

Is the role of human RNase H2 restricted to its enzyme activity?

In human cells, ribonuclease (RNase) H2 complex is the predominant source of RNase H activities with possible roles in nucleic acid metabolism to preserve genome stability and to prevent immune activation. Dysfunction mutations in any of the three subunits of human RNase H2 complex can result in embryonic/perinatal lethality or cause Aicardi-Goutières syndrome (AGS). Most recently, increasing findings have shown that human RNase H2 proteins play roles beyond the RNase H2 enzymatic activities in health and disease. Firstly, the biochemical and structural properties of human RNase H2 proteins allow their interactions with various partner proteins that may support functions other than RNase H2 enzymatic activities. Secondly, the disparities of clinical presentations of AGS with different AGS-mutations and the biochemical and structural analysis of AGS-mutations, especially the results from both AGS-knockin and RNase H2-null mouse models, suggest that human RNase H2 complex has certain cellular functions beyond the RNase H2 enzymatic activities to prevent the innate-immune-mediated inflammation. Thirdly, the subunit proteins RNASEH2A and RNASEH2B respectively, not related to the RNase H2 enzymatic activities, have been shown to play a certain role in the pathophysiological processes of different cancer types. In this minireview, we aims to provide a brief overview of the most recent investigations into the biological functions of human RNase H2 proteins and the underlying mechanisms of their actions, emphasizing on the new insights into the roles of human RNase H2 proteins playing beyond the RNase H2 enzymatic activities in health and disease.

New trends in nucleoside biotechnology.

This review focuses on new trends in nucleoside biotechnology, which have emerged during the last decade. Continuously growing interest in the study of this class of compounds is fueled by a number of factors: ( i ) a growing need for large-scale production of natural 2 ' -deoxy- ß -D-ribonucleosides as well as their analogs with modifications in the carbohydrate and base fragments, which can then be used for the synthesis and study of oligonucleotides, including short-interfering RNA (siRNA), microRNA (miRNA), etc.; ( ii ) a necessity for the development of efficient practical technologies for the production of biologically important analogs of natural nucleosides, including a number of anticancer and antiviral drugs; ( iii ) a need for further study of known and novel enzymatic transformations and their use as tools for the efficient synthesis of new nucloside analogs and derivates with biomedical potential. This article will review all of these aspects and also include a brief retrospect of this field of research.