DNA in cells is supercoiled and constrained into loops and this supercoiling and looping influence every aspect of DNA activity. We show here that negative supercoiling transmits mechanical stress along the DNA backbone to disrupt base pairing at specific distant sites. Cooperativity among distant sites localizes certain sequences to superhelical apices. Base pair disruption allows sharp bending at superhelical apices, which facilitates DNA writhing to relieve torsional strain. The coupling of these processes may help prevent extensive denaturation associated with genomic instability. Our results provide a model for how DNA can form short loops, which are required for many essential processes, and how cells may use DNA loops to position nicks to facilitate repair. Furthermore, our results reveal a complex interplay between site-specific disruptions to base pairing and the 3-D conformation of DNA, which influences how genomes are stored, replicated, transcribed, repaired, and many other aspects of DNA activity.

In addition to regulatory or accessory proteins, some complex retroviruses gain a repertoire of micro-RNAs (miRNAs) to regulate and control virus–host interactions for efficient replication and spread. In particular, bovine and simian foamy viruses (BFV and SFV) have recently been shown to express a diverse set of RNA polymerase III-directed miRNAs, some with a unique primary miRNA double-hairpin, dumbbell-shaped structure not known in other viruses or organisms. While the mechanisms of expression and structural requirements have been studied, the functional importance of these miRNAs is still far from understood. Here, we describe the in silico identification of BFV miRNA targets and the subsequent experimental validation of bovine Ankyrin Repeat Domain 17 (ANKRD17) and Bax-interacting factor 1 (Bif1) target genes in vitro and, finally, the suppression of ANKRD17 downstream genes in the affected pathway. Deletion of the entire miRNA cassette in the non-coding part of the U3 region of the long terminal repeats attenuated replication of corresponding BFV mutants in bovine cells. This repression can be almost completely trans-complemented by the most abundant miRNA BF2-5p having the best scores for predicted and validated BFV miRNA target genes. Deletion of the miRNA cassette does not grossly affect particle release and overall particle composition.

Genomic instability and genetic mutations can lead to exhibition of several cancer hallmarks in affected cells such as sustained proliferative signaling, evasion of growth suppression, activated invasion, deregulation of cellular energetics, and avoidance of immune destruction. Similar biological changes have been observed to be a result of pathogenic viruses and, in some cases, have been linked to virus-induced cancers. Human endogenous retroviruses (HERVs), once external pathogens, now occupy more than 8% of the human genome, representing the merge of genomic and external factors. In this review, we outline all reported effects of HERVs on cancer development and discuss the HERV targets most suitable for cancer treatments as well as ongoing clinical trials for HERV-targeting drugs. We reviewed all currently available reports of the effects of HERVs on human cancers including solid tumors, lymphomas, and leukemias. Our review highlights the central roles of HERV genes, such as gag, env, pol, np9, and rec in immune regulation, checkpoint blockade, cell differentiation, cell fusion, proliferation, metastasis, and cell transformation. In addition, we summarize the involvement of HERV long terminal repeat (LTR) regions in transcriptional regulation, creation of fusion proteins, expression of long non-coding RNAs (lncRNAs), and promotion of genome instability through recombination.

Human endogenous retroviruses (HERVs), which in the past have inserted themselves in various regions of the human genome, are to various degrees activated in virtually every cancer type. While a centralized naming system and resources summarizing HERV levels in cancers are lacking, the CancerHERVdb database provides a consolidated resource for cross-study comparisons, data exploration, and targeted searches of HERV activation.

No abstract

DNA supercoiling affects DNA metabolism yet much about how it does so is unknown. Using 336 bp DNA minicircles covering a range of positive to negative supercoiling, we unveiled the first three-dimensional structures of supercoiled DNA using cryo-electron tomography. With supercoiling, DNA can form far more bent and contorted shapes than predicted. We sought to understand how the interplay of DNA sequence and supercoiling drives the formation of these shapes using coarse-grained simulations and biochemical probing. Base pair disruptions indicate regions of high bending, as localized denaturation (from base flipping) creates flexible hinges. At the same time, sharp bending at the apices of highly writhed DNA circles leads to broken base pairs. Probing with nuclease Bal-31 revealed exposed bases as a function of supercoiling. Bal31 cleaved all the negatively supercoiled 336 bp minicircles but the rate increased beyond a distinct negative supercoiling threshold. This threshold shifted to more negative supercoiling for 672 bp minicircles with inherently less curvature, demonstrating the relationship between bending and base accessibility. A sharp positive supercoiling threshold was required for Bal-31 cleavage to even occur. We mapped Bal-31 cleavage sites and, using coarse-grained simulations, determined the DNA register of our cryo-electron micrograph images. Our data reveal two hotspots of Bal-31 cleavage located 180 apart along the DNA circumference, suggesting that exposed bases are predominantly located at superhelical apices and that a particular three-dimensional conformation is dominant. The relative probability of Bal-31 cleaving at either site varied as a function of supercoiling. Together these data reveal the interplay among sequence, supercoiling, and shape, resulting in conformational changes that should profoundly influence DNA interactions with proteins. Understanding these changes could facilitate the design of supercoiling-dependent DNA nanostructures for gene therapy.

Sarcomas are relatively rare malignancies accounting for about 1% of all cancer diagnoses. Studies on sarcomas comprising large cohorts covering extended time periods are lacking. Therefore, this study aimed to evaluate the impact of demographic, behavioral, and clinical characteristics on overall survival (OS) among individuals diagnosed with soft tissue sarcoma (STS) or bone sarcoma at the Moffitt Cancer Center between 1986 and 2014. Unadjusted and multivariable Cox proportional hazard regression (CPHR) models were constructed to generate hazard ratios (HRs) and 95% confidence intervals (CIs) to evaluate associations between a range of demographic, behavioral, and clinical characteristics, and OS. Additionally, Kaplan–Meier survival curves, associated log-rank statistics, and adjusted CPHR models were generated by time periods based on the year of first contact (1986–1994, 1995–1999, 2000–2005, 2006–2010, 2011–2014) to evaluate for temporal differences in OS. Of the 2570 patients, 2037 were diagnosed with STS, whereas 533 were diagnosed with bone sarcoma. At the time of analysis, 50% of the population were alive. In multivariable analyses, we observed poorer survival for patients ≥ 40 years of age (HR = 1.54, 95% CI = 1.34–1.78), current smokers (HR = 1.18, 95% CI = 1.01–1.37), patients with metastasis (HR = 2.19, 95% CI = 1.95–2.47), and patients not receiving first-line surgery treatment (HR = 2.11, 95% CI = 1.82–2.45). We discovered limited improvements in OS over time among individuals diagnosed with STS or bone sarcomas with the exception of gastrointestinal stromal tumors (GIST), which showed a significant improvement in OS across time periods (p = 0.0034). Overall, we identified well-established characteristics associated with OS (e.g., metastasis) in addition to factors (e.g., smoking status) not previously reported to impact OS. Improvements in survival over time have been relatively modest, suggesting the need for improved therapeutic options, especially for those diagnosed with less frequent sarcomas.

The PDF Data Extractor (PDE) R package is designed to perform comprehensive literature reviews for scientists at any stage in a user-friendly way. The PDE_analyzer_i() function permits the user to filter and search thousands of scientific articles using a simple user interface, requiring no bioinformatics skills. In the additional PDE_reader_i() interface, the user can then quickly browse the sentences with detected keywords, open the full-text article, when required, and convert tables conveniently from PDF files to Excel sheets (pdf2table). Specific features of the literature analysis include the adaptability of analysis parameters and the detection of abbreviations of search words in articles. In this article, we demonstrate and exemplify how the PDE package allows the user-friendly, efficient, and automated extraction of meta-data from full-text articles, which can aid in summarizing the existing literature on any topic of interest. As such, we recommend the use of the PDE package as the first step in conducting an extensive review of the scientific literature. The PDE package is available from the Comprehensive R Archive Network at https://CRAN.R-project.org/package=PDE.