The Prp19C subunit Syf2 and the Prp19C-associated protein Cwc15 function in TREX occupancy and transcription elongation.

The Prp19 complex (Prp19C) also named NineTeen Complex (NTC) is conserved from yeast to human and functions in many different processes such as genome stability, splicing and transcription elongation. In the latter, Prp19C ensures TREX occupancy at transcribed genes. TREX in turn couples transcription to nuclear mRNA export by recruiting the mRNA exporter to transcribed genes and consequently to nascent mRNAs. Here, we assess the function of the nonessential Prp19C subunit Syf2 and the nonessential Prp19C-associated protein Cwc15 in the interaction of Prp19C and TREX with the transcription machinery, Prp19C and TREX occupancy as well as transcription elongation. Whereas both proteins are important for Prp19C-TREX interaction, Syf2 is needed for full Prp19C occupancy, and Cwc15 is important for the interaction of Prp19C with RNA polymerase II and TREX occupancy. These partially overlapping functions are corroborated by a genetic interaction between Δcwc15 and Δsyf2. Finally, Cwc15 also interacts genetically with the transcription elongation factor Dst1 and functions in transcription elongation. In summary, we uncover novel roles of the Prp19C component Syf2 and the Prp19C-associated protein Cwc15 in Prp19C's function in transcription elongation.

Breast Cancer Prognostic Hub Genes Identified by Integrated Transcriptomic and Weighted Network Analysis: A Road Toward Personalized Medicine.

Breast cancer (BC) is the second-most common type and among the leading causes of worldwide cancer-related deaths. There is marked person-to-person variability in susceptibility to, and phenotypic expression and prognosis of BC, a predicament that calls for personalized medicine and individually tailored therapeutics. In this study, we report new observations on prognostic hub genes and key pathways involved in BC. We used the data set GSE109169, comprising 25 pairs of BC and adjacent normal tissues. Using a high-throughput transcriptomic approach, we selected data on 293 differentially expressed genes to establish a weighted gene coexpression network. We identified three age-linked modules where the light-gray module strongly correlated with BC. Based on the gene significance and module membership features, peptidase inhibitor 15 (PI15) and KRT5 were identified as our hub genes from the light-gray module. These genes were further verified at transcriptional and translational levels across 25 pairs of BC and adjacent normal tissues. Their promoter methylation profiles were assessed based on various clinical parameters. In addition, these hub genes were used for Kaplan-Meier survival analysis, and their correlation with tumor-infiltrating immune cells was investigated. We found that PI15 and KRT5 may be potential biomarkers and potential drug targets. These findings call for future research in a larger sample size, which could inform diagnosis and clinical management of BC, thus paving the way toward personalized medicine.

Genome-wide scan for potential CD4+ T-cell vaccine candidates in Candida auris by exploiting reverse vaccinology and evolutionary information.

Candida auris is a globally emerging fungal pathogen responsible for causing nosocomial outbreaks in healthcare associated settings. It is known to cause infection in all age groups and exhibits multi-drug resistance with high potential for horizontal transmission. Because of this reason combined with limited therapeutic choices available, C. auris infection has been acknowledged as a potential risk for causing a future pandemic, and thus seeking a promising strategy for its treatment is imperative. Here, we combined evolutionary information with reverse vaccinology approach to identify novel epitopes for vaccine design that could elicit CD4+ T-cell responses against C. auris. To this end, we extensively scanned the family of proteins encoded by C. auris genome. In addition, a pathogen may acquire substitutions in epitopes over a period of time which could cause its escape from the immune response thus rendering the vaccine ineffective. To lower this possibility in our design, we eliminated all rapidly evolving genes of C. auris with positive selection. We further employed highly conserved regions of multiple C. auris strains and identified two immunogenic and antigenic T-cell epitopes that could generate the most effective immune response against C. auris. The antigenicity scores of our predicted vaccine candidates were calculated as 0.85 and 1.88 where 0.5 is the threshold for prediction of fungal antigenic sequences. Based on our results, we conclude that our vaccine candidates have the potential to be successfully employed for the treatment of C. auris infection. However, in vivo experiments are imperative to further demonstrate the efficacy of our design.

Role of the Pangolin in Origin of SARS-CoV-2: An Evolutionary Perspective.

After the recent emergence of SARS-CoV-2 infection, unanswered questions remain related to its evolutionary history, path of transmission or divergence and role of recombination. There is emerging evidence on amino acid substitutions occurring in key residues of the receptor-binding domain of the spike glycoprotein in coronavirus isolates from bat and pangolins. In this article, we summarize our current knowledge on the origin of SARS-CoV-2. We also analyze the host ACE2-interacting residues of the receptor-binding domain of spike glycoprotein in SARS-CoV-2 isolates from bats, and compare it to pangolin SARS-CoV-2 isolates collected from Guangdong province (GD Pangolin-CoV) and Guangxi autonomous regions (GX Pangolin-CoV) of South China. Based on our comparative analysis, we support the view that the Guangdong Pangolins are the intermediate hosts that adapted the SARS-CoV-2 and represented a significant evolutionary link in the path of transmission of SARS-CoV-2 virus. We also discuss the role of intermediate hosts in the origin of Omicron.

Alveolar Regeneration in COVID-19 Patients: A Network Perspective.

A viral infection involves entry and replication of viral nucleic acid in a host organism, subsequently leading to biochemical and structural alterations in the host cell. In the case of SARS-CoV-2 viral infection, over-activation of the host immune system may lead to lung damage. Albeit the regeneration and fibrotic repair processes being the two protective host responses, prolonged injury may lead to excessive fibrosis, a pathological state that can result in lung collapse. In this review, we discuss regeneration and fibrosis processes in response to SARS-CoV-2 and provide our viewpoint on the triggering of alveolar regeneration in coronavirus disease 2019 (COVID-19) patients.

Mud2 functions in transcription by recruiting the Prp19 and TREX complexes to transcribed genes.

The different steps of gene expression are intimately linked to coordinate and regulate this complex process. During transcription, numerous RNA-binding proteins are already loaded onto the nascent mRNA and package the mRNA into a messenger ribonucleoprotein particle (mRNP). These RNA-binding proteins are often also involved in other steps of gene expression than mRNA packaging. For example, TREX functions in transcription, mRNP packaging and nuclear mRNA export. Previously, we showed that the Prp19 splicing complex (Prp19C) is needed for efficient transcription as well as TREX occupancy at transcribed genes. Here, we show that the splicing factor Mud2 interacts with Prp19C and is needed for Prp19C occupancy at transcribed genes in Saccharomyces cerevisiae. Interestingly, Mud2 is not only recruited to intron-containing but also to intronless genes indicating a role in transcription. Indeed, we show for the first time that Mud2 functions in transcription. Furthermore, these functions of Mud2 are likely evolutionarily conserved as Mud2 is also recruited to an intronless gene and interacts with Prp19C in Drosophila melanogaster. Taken together, we classify Mud2 as a novel transcription factor that is necessary for the recruitment of mRNA-binding proteins to the transcription machinery. Thus, Mud2 is a multifunctional protein important for transcription, splicing and most likely also mRNP packaging.