Resolution of coronavirus disease 2019 (COVID-19).

Introduction: Coronavirus disease 2019 (COVID-19) was first detected in China in December, 2019, and declared as a pandemic by the World Health Organization (WHO) on March 11, 2020. The current management of COVID-19 is based generally on supportive therapy and treatment to prevent respiratory failure. The effective option of antiviral therapy and vaccination are currently under evaluation and development.

Targeting SOCS Proteins to Control JAK-STAT Signalling in Disease.

Defective regulation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway in cancers, haematological diseases, and chronic inflammatory conditions highlights its clinical significance. While several biologic and small molecule therapeutics targeting this pathway have been developed, these have several limitations. Therefore, there is a need to identify new targets for intervention.

Aminoglycoside-mediated promotion of translation readthrough occurs through a non-stochastic mechanism that competes with translation termination.

Attempts have been made to treat nonsense-associated genetic disorders by chemical agents and hence an improved mechanistic insight into the decoding of readthrough signals is essential for the identification and characterisation of factors for the treatment of these disorders. To identify either novel compounds or genes that modulate translation readthrough, we have employed dual reporter-based high-throughput screens that use enzymatic and fluorescence activities and screened bioactive National Institute of Neurological Disease Syndrome (NINDS) compounds (n = 1000) and siRNA (n = 288) libraries. Whilst siRNAs targeting kinases such as CSNK1G3 and NME3 negatively regulate readthrough, neither the bioactive NINDS compounds nor PTC124 promote readthrough.

Mammary gland selective excision of c-jun identifies its role in mRNA splicing.

The c-jun gene regulates cellular proliferation and apoptosis via direct regulation of cellular gene expression. Alternative splicing of pre-mRNA increases the diversity of protein functions, and alternate splicing events occur in tumors. Here, by targeting the excision of the endogenous c-jun gene within the mouse mammary epithelium, we have identified its selective role as an inhibitor of RNA splicing.

Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.

Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation.

Ataxia oculomotor apraxia type 2 (AOA2) is an autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia and oculomotor apraxia. The gene mutated in AOA2, SETX, encodes senataxin, a putative DNA/RNA helicase which shares high homology to the yeast Sen1p protein and has been shown to play a role in the response to oxidative stress. To investigate further the function of senataxin, we identified novel senataxin-interacting proteins, the majority of which are involved in transcription and RNA processing, including RNA polymerase II.

Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension.

Heterozygous germline defects in a gene encoding a type II receptor for bone morphogenetic proteins (BMPR-II) underlie the majority of inherited cases of the vascular disorder known as pulmonary arterial hypertension (PAH). However, the precise molecular consequences of PAH causing mutations on the function of the receptor complex remain unclear. We employed novel enzymatic and fluorescence activity based techniques to assess the impact of PAH mutations on pre-mRNA splicing, nonsense-mediated decay (NMD) and receptor complex interactions.

HnRNP G and Tra2beta: opposite effects on splicing matched by antagonism in RNA binding.

The hnRNP G family comprises three closely related proteins, hnRNP G, RBMY and hnRNP G-T. We showed previously that they interact with splicing activator proteins, particularly hTra2beta, and suggested that they were involved in regulating Tra2-dependent splicing. We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of several exons, both being able to act as either an activator or a repressor.