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Intronic Polyadenylation Isoforms and Microproteins in Cell Response to Cisplatin

Core Concepts
The author explores the role of intronic polyadenylation isoforms in producing microproteins and their involvement in cell response to cisplatin, revealing a novel paradigm of miP-5’UTR-IPA genes.
Transcript isoforms generated by intronic polyadenylation (IPA) are regulated by cisplatin, leading to the production of microproteins encoded by small open reading frames. Cisplatin upregulates IPA isoforms that encode microproteins impacting cell response to the drug. The study identifies 156 genes producing both canonical protein-coding mRNA and microprotein-coding 5’UTR-located IPA isoform regulated by cisplatin. The PHF20 and PRKAR1B genes produce microproteins from their 5’UTR-located IPA isoforms, affecting cisplatin sensitivity. Polysome profiling shows that these microproteins are associated with light polysomes, indicating active translation. Mutations in the sORFs of these microproteins lead to increased cell survival to cisplatin, highlighting their functional significance.
Cisplatin upregulates IPA:LE isoform ratio in many genes. A subset of IPA isoforms are depleted in heavy polysomes and terminate in the annotated 5’UTR part of genes. The PHF20 and PRKAR1B 5’UTR-IPA isoforms are enriched in light polysomes.
"Cisplatin widely regulates alternative splicing but little is known about its effects on IPA isoforms." "Intronic polyadenylation constitutes a potential source of unexplored microprotein production." "The novel paradigm of miP-5’UTR-IPA genes reveals insights into cancer cell response mechanisms."

Deeper Inquiries

What implications do intronic polyadenylation isoforms have for cancer therapy beyond cisplatin treatment

Intronic polyadenylation isoforms have significant implications for cancer therapy beyond cisplatin treatment. These isoforms can potentially serve as novel targets for therapeutic intervention in various types of cancers. By regulating gene expression and protein production, IPA isoforms may play crucial roles in tumor development, progression, and response to treatment. Targeting specific IPA isoforms could offer a unique approach to modulating key pathways involved in cancer growth and metastasis. Additionally, understanding the functional significance of these isoforms could lead to the identification of new biomarkers for cancer diagnosis and prognosis.

Could there be potential drawbacks or limitations to targeting microproteins produced by IPA isoforms for therapeutic purposes

While targeting microproteins produced by IPA isoforms holds great promise for therapeutic purposes, there are potential drawbacks and limitations that need to be considered. One limitation is the challenge of specifically targeting small proteins with unique functions without affecting essential cellular processes or causing unintended side effects. The short length of microproteins may also make them less stable or more susceptible to degradation within cells, which could impact their effectiveness as therapeutic targets. Furthermore, the diverse functions and regulatory mechanisms associated with microproteins encoded by IPA isoforms require thorough characterization to ensure safe and effective targeting strategies.

How might understanding the translation outcomes of IPA isoforms contribute to our knowledge of cellular stress responses

Understanding the translation outcomes of intronic polyadenylation (IPA) isoforms contributes significantly to our knowledge of cellular stress responses by uncovering novel mechanisms underlying gene regulation during stress conditions such as exposure to genotoxic agents like cisplatin. The identification of IPA isoforms that encode microproteins provides insights into how cells respond at a molecular level to external stimuli or challenges. This knowledge enhances our understanding of the intricate interplay between transcriptional control, translational regulation, and cellular adaptation under stress conditions. By elucidating how specific IPA isoforms are translated into functional microproteins that influence cell survival or sensitivity to stressors like cisplatin, researchers can gain valuable information about potential targets for modulating cellular responses in disease states such as cancer or other disorders characterized by dysregulated stress signaling pathways. Overall, studying the translation outcomes of IPA isoform sheds light on previously unrecognized aspects of cellular biology related to stress responses and opens up new avenues for investigating therapeutic interventions aimed at manipulating these processes for clinical benefit.