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bioRxiv · 10.1101/2025.03.11.642677

Transcriptional stress induces the overexpression of novel lncRNAs that regulate the BRCA1 locus

Cruz-Ruiz, S.·Vidal, R.·Fulan-Magaril, M.·Lis, J. T.·Zurita, M.
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Abstract

BackgroundRegulation of gene transcription is an essential early response to a broad variety of cellular stress. Paradoxically, pharmacological inhibition of an RNA polymerase II transcription initiation factor, XPB, induces a stress response that overactivates transcription of a subset of transcripts, including lncRNAs. However, the mechanisms enabling selective transcription under global initiation blockade, and the regulatory contribution of lncRNAs, remain unclear. ResultsGenome-wide assays in human cells treated with triptolide, which disrupts XPB translocase activity within TFIIH, revealed that a subset of genes continues to be transcribed independently of XPB activity, driven by thermodynamically unstable promoters. These promoters account for paradoxical transcriptional upregulation during global transcriptional inhibition. Among XPB-resistant transcripts, we identified previously uncharacterized regulatory long non-coding RNAs--TILR-1, TILR-2, and LINC00910--that are conserved in primates and display interdependent expression. Together, these lncRNAs form a coordinated regulatory module that modulates transcription at the BRCA1 locus. Disruption of expression of these lncRNAs promotes cell proliferation and survival, phenocopying reduced expression of BRCA1 locus genes. This lncRNA network is also activated by distinct transcriptional inhibitors indicating a shared transcriptional stress-responsive mechanism. ConclusionsUnstable promoters sustain transcription in the absence of XPB, defining an XPB-independent transcriptional program that includes a transcriptional stress-responsive lncRNA regulatory network. This mechanism enables selective gene activation during global transcriptional inhibition, with the BRCA1 locus representing one example, and suggests a broader transcriptional switch involved in cellular adaptation to transcriptional stress.

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Cruz-Ruiz, S., Vidal, R., Fulan-Magaril, M., Lis, J. T., Zurita, M.. 2025-03-13. Transcriptional stress induces the overexpression of novel lncRNAs that regulate the BRCA1 locus. https://doi.org/10.1101/2025.03.11.642677

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