Biology subjects

Sathaseevan, A.

Publications and source records attributed to Sathaseevan, A..

3 recordsLinked to original sources

bioRxiv2025

A stress-dependent postembryonic role for the core CPA factor CFIM-1 in germline integrity

Post-transcriptional processing of pre-mRNAs generates a diversity of 3 UTR transcript isoforms that can vary in their function and stability. The differential enrichment of transcript isoforms has been implicated in diseases ranging from cancer to neurodevelopmental disorders. However, the post-embryonic developmental roles of the core ensemble of cleavage and polyadenylation (CPA) factors that mediate these post-transcriptional changes remain poorly characterized. Here, we report a stress- dependent role for the core CPA factor CFIM-1 in germline integrity in Caenorhabditis elegans. Total loss-of-function of cfim-1 elicits a temperature-sensitive sterile phenotype in hermaphrodites. These changes in brood size are accompanied by broad sperm, oocyte and germline morphology defects. Surveying the transcriptome of cfim-1(lf) worms, we uncover changes in transcript isoform abundance for dozens of genes with known functions related to the development and maintenance of these structures, consistent with a model in which post-transcriptional regulation of target genes via cfim- 1 is crucial to the development and maintenance of germline integrity. Our findings collectively define a novel post-embryonic role for a core CPA factor in tissue-specific development.

developmental biology↗

bioRxiv2023

Regulation of the hypertonic stress response by the 3' mRNA cleavage and polyadenylation complex

Maintenance of osmotic homeostasis is one of the most aggressively defended homeostatic setpoints in physiology. One major mechanism of osmotic homeostasis involves the upregulation of proteins that catalyze the accumulation of solutes called organic osmolytes. To better understand how osmolyte accumulation proteins are regulated, we conducted forward genetic screen in C. elegans for mutants with no induction of osmolyte biosynthesis gene expression (Nio mutants). nio-3 mutants encoded a missense mutation in cpf-2/CstF64 while nio-7 mutants encoded a missense mutation in symk-1/Symplekin. Both cpf-2 and symk-1 are nuclear components of the highly conserved 3 mRNA cleavage and polyadenylation complex. cpf-2 and symk-1 block the hypertonic induction of gpdh-1 and other osmotically induced mRNAs, suggesting they act at the transcriptional level. We generated a functional auxin-inducible degron (AID) allele for symk-1 and found that acute, post-developmental degradation in the intestine and hypodermis was sufficient to cause the Nio phenotype. symk-1 and cpf-2 exhibit genetic interactions that strongly suggest they function through alterations in 3 mRNA cleavage and/or alternative polyadenylation. Consistent with this hypothesis, we find that inhibition of several other components of the mRNA cleavage complex also cause a Nio phenotype. cpf-2 and symk-1 specifically affect the osmotic stress response since heat shock-induced upregulation of a hsp-16.2::GFP reporter is normal in these mutants. Our data suggest a model in which alternative polyadenylation of one or more mRNAs is essential to regulate the hypertonic stress response.

physiology↗

bioRxiv2020

Alternative polyadenylation is a determinant of oncogenic Ras function

Alternative polyadenylation of pre-mRNA has been recently shown to play important roles in development and cancer. Activating mutations in the Ras oncogene are common drivers of many human cancers but the mechanisms by which they cooperate with alternative polyadenylation are not known. By exploiting the genetics of C. elegans, we identified cfim-1/CFIm25, a subunit of the alternative polyadenylation machine, as a key determinant of hyperactive Ras function. Ablation of cfim-1 increased penetrance of multivulva phenotype in let-60/Ras gain-of-function (gf) mutant through shortening of transcripts at the 3 untranslated region, including p21 activated kinase pak-1/PAK1 and multidrug transporter mrp-5/ABCC1. Depletion of CFIm25 in human KRAS-driven cancer cells resulted in a similar shortening of 3 untranslated regions in the PAK1 and ABCC1 transcripts, which caused an epithelial-to-mesenchymal transition and increased cell migration. Exploiting the mechanisms by which alternative polyadenylation affects activated oncogene output could offer novel approaches for the treatment of Ras-driven tumors.

cancer biology↗