Publications by authors named "N V Rajeshkumar"
Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22.
Cell Chem Biol
July 2025
Ribosome biosynthesis is a cancer vulnerability targeted by inhibiting RNA polymerase I (Pol I) transcription. We developed specific Pol I inhibitors that activate a ribotoxic stress pathway to uncover drivers of sensitivity. Integrating multi-omics and drug response data from a large cancer cell panel, we found that RPL22 frameshift mutations confer Pol I inhibitor sensitivity.
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- Ribosome biosynthesis is targeted as a vulnerability in cancer by inhibiting RNA polymerase I (Pol I) transcription, leading to the identification of specific Pol I inhibitors.
- Research showed that frameshift mutations in microsatellite unstable cancers increase sensitivity to these Pol I inhibitors, as RPL22 interacts with 28S rRNA and regulates RNA splicing.
- RPL22 deficiency triggers a complex response, promoting splicing changes and activating a tumor suppressive pathway through the inhibition of rRNA synthesis, revealing a key connection between ribosomal activity and mRNA splicing processes.
RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) into the 47S ribosomal RNA (rRNA) precursor. Further processing produces the 28S, 5.8S, and 18S rRNAs that are assembled into mature ribosomes.
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- Polymorphism in ribosomal RNA (rRNA) genes enhances adaptability and survival under stress, with genetic diversity arising from variations in the multicopy gene.
- Researchers identified four rDNA copies on chromosome 21 that were 99% similar to a new reference sequence and analyzed variants in a sample of 2504 individuals from diverse populations.
- A total of 3791 variant positions were found, particularly in flexible areas of the 28S rRNA, suggesting ongoing evolutionary changes and highlighting the need for further functional studies on how these variants influence ribosome function.
Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma.
Br J Cancer
February 2020
Background: The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling.
Methods: Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel.