Biomedical subjects

Athma A Pai

Publications and source records attributed to Athma A Pai.

3 recordsLinked to original sources

PubMed2026

Pervasive noise in human pre-mRNA splice site selection.

RNA splicing has historically been thought to be highly efficient and accurate, with little opportunity for deviation from regulated alternative splicing. This dogma has been challenged by recent observations that biological noise may contribute substantially to transcriptome diversity. However, quantitative understanding of stochastic splicing variation is challenging because these transcripts are likely subject to rapid degradation. Here, we use deep sequencing across RNA compartments to track splicing intermediates in human cells and see abundant cryptic splicing associated with genomic features that promote splicing noise. We observe pervasive usage of low-fidelity splice sites, likely due to stochasticity in recruitment or binding of the spliceosome. These sites are turned over quickly and show evidence for nuclear and cytoplasmic degradation, suggesting widespread surveillance and rapid quality control of non-productive transcripts. Our findings provide insights into the propensity for error in RNA processing mechanisms and regulation of alternative splice sites across a gene.

Humans↗

PubMed2025

RNA Pol II inhibition activates cell death independently from the loss of transcription.

RNA Pol II-mediated transcription is essential for eukaryotic life. Although loss of transcription is thought to be universally lethal, the associated mechanisms promoting cell death are not yet known. Here, we show that death following the loss of RNA Pol II activity does not result from dysregulated gene expression. Instead, it occurs in response to loss of the hypophosphorylated form of Rbp1 (also called RNA Pol IIA). Loss of RNA Pol IIA exclusively activates apoptosis, and expression of a transcriptionally inactive version of Rpb1 rescues cell viability. Using functional genomics, we identify the mechanisms driving lethality following the loss of RNA Pol IIA, which we call the Pol II degradation-dependent apoptotic response (PDAR). Using the genetic dependencies of PDAR, we identify clinically used drugs that owe their lethality to a PDAR-dependent mechanism. Our findings unveil an apoptotic signaling response that contributes to the efficacy of a wide array of anti-cancer therapies.

RNA Polymerase II↗

PubMed2025

Pervasive noise in human splice site selection.

RNA splicing has historically been thought to be highly efficient and accurate, with little opportunity for deviation from regulated alternative splicing decisions. This dogma has been challenged by recent observations that suggest that biological noise may contribute substantially to transcriptome diversity. However, quantitative understanding of stochastic variations in splicing is challenging because these transcripts are likely subject to rapid degradation. Here, we use ultra-deep sequencing across RNA compartments to track splicing intermediates in human cells and see abundant cryptic splicing associated with genomic features that promote splicing noise. We observe pervasive usage of low-fidelity splice sites, likely due to stochasticity in recruitment or binding of the spliceosome. These sites are most likely degraded in the nucleus rather than targeted by translation-dependent degradation processes, suggesting widespread surveillance and rapid quality control of non-productive RNA transcripts. Our findings provide unprecedented insights into the propensity for error in RNA processing mechanisms and the regulation of alternative splice sites across a gene.

Journal Article↗