Biology subjects

Liudkovska, V.

Publications and source records attributed to Liudkovska, V..

3 recordsLinked to original sources

bioRxiv2024

TENT-5 regulates the expression of male-specific genes in Caenorhabditis elegans

Polyadenylation is an important post-transcriptional process that governs mRNA stability and expression. Advancements in direct RNA sequencing in recent years have clarified many aspects of this intricate regulation, revealing the influence of various factors. Here, we used Nanopore Direct RNA Sequencing to investigate the association between genome-wide mRNA poly(A) tail profiles and sexual dimorphism in Caenorhabditis elegans. Our results demonstrate sex-dependent differences in both gene expression and poly(A) tail metabolism. Notably, we discovered that cytoplasmic poly(A) polymerase TENT-5 regulates multiple male-specific transcripts, predominantly encoding putative seminal fluid components with predicted extracellular localization. TENT-5 expression in male-specific tissues, such as seminal vesicle and vas deference, corroborates its functional significance. Intriguingly, despite extensive TENT-5-mediated polyadenylation of male-specific transcripts, males devoid of TENT-5 show no abnormalities in mating behavior, sperm morphology, or fertility. Our findings suggest that TENT-5 plays a role in regulating sex-related processes in males, although the physiological consequences remain to be fully elucidated.

molecular biology↗

bioRxiv2023

Recurrent Multiple Myeloma DIS3 alleles arise early but are later counter-selected due to toxicity

DIS3 encodes an essential ribonucleic subunit of the nuclear exosome complex, responsible for degrading RNA in the nucleus. Somatic DIS3 mutations drive translocations in B cells, leading to multiple myeloma (MM). Clinical data analysis reveals that 42% of DIS3 mutations occur at three recurrent residues (D479, D488, and R780). These mutations, deactivating DIS3 exonucleolytic activity, are never homozygous, often appearing as minor subclones in advanced MM. Surprisingly, mutant DIS3 alleles undergo loss-of-heterozygosity, correlating with frequent del(13q) encompassing DIS3. Overexpression of wild-type DIS3 enhances growth and viability of DIS3-mutated MM cells, while CRISPR-mediated knock-out of the mutant variant, followed by longitudinal co-culture, replicates its elimination through counterselection, observed in the natural course of the disease. In mice, the heterozygous DIS3 D479 mutation is embryolethal, confirming its dominant toxic effects. Transcriptome analysis of patients and cell lines reveals specific transcriptional signatures of DIS3 mutations with accumulation of non-coding unstable RNA species and including secondary indications of decreased proliferation. All these signatures are reversible upon mutant DIS3 loss-of-heterozygosity. DIS3 is an intriguing hit-and-run oncogene that drives MM, but is subsequently eliminated during clonal evolution.

molecular biology↗

bioRxiv2023

PP2A inhibition instructs spliceosome phosphorylation to create splicing vulnerability in colon adenocarcinoma

Protein phosphatase 2A (PP2A) is a versatile enzyme affecting many aspects of cellular physiology. However, it remains unclear which of the cellular processes are most perturbed upon PP2A inhibition and how these perturbations could be exploited therapeutically. We report an unanticipated sensitivity of the splicing machinery to phosphorylation changes in response to PP2A inhibition by LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. Altered phosphorylation endows LB-100-treated colorectal adenocarcinoma cells with differential splicing patterns. In PP2A-inhibited cells, over 1000 events of exon skipping and intron retention affect regulators of genomic integrity. Finally, LB-100-evoked alternative splicing is predicted to be a source of neoantigens that can improve cancer treatment responses to immune modulators. Our findings provide a potential explanation for the pre-clinical and clinical observations that PP2A inhibition sensitizes cancer cells to immune checkpoint blockade and genotoxic agents.

cancer biology↗