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bioRxiv · 10.64898/2026.05.26.728043

rDNA breaks activate dsRNA pattern recognition through sense-antisense transcription

Chen, J.·Kim, S.·Chen, S.·Mo, Z.·Jiang, Y.·Liu, K. F.·Li, Q.·Greenberg, R. A.
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Abstract

Myriad DNA damaging chemo- and radio- therapies interfere with ribosomal RNA (rRNA) transcription and processing, yet the biological consequences of these phenomena remain unclear. Here we show that aberrant transcripts emanating from rDNA breaks engage double-stranded RNA pattern recognition receptors, melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene I (RIG-I) to activate immune signaling. rDNA damage abolishes full-length rRNA synthesis while generating truncated sense-antisense rRNA transcripts, whose accumulation is restrained by ATM and ATR kinase activities. Purification of the endogenous MDA5-filament coupled with sequencing identified complementary sense and antisense rRNA transcripts that terminate and initiate near the break site, respectively. This implicates aberrant rRNA species as a major source of damage induced endogenous ligands for dsRNA pattern recognition and establishes a mechanism by which nucleolar stress is coupled to immune signaling.

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Chen, J., Kim, S., Chen, S., Mo, Z., Jiang, Y., Liu, K. F., Li, Q., Greenberg, R. A.. 2026-05-28. rDNA breaks activate dsRNA pattern recognition through sense-antisense transcription. https://doi.org/10.64898/2026.05.26.728043

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