snRNA Orchestrates IRAK1 mediated ATM Activation to Promote Accurate Repair within Transcriptionally Active Chromatin

Description

Genomic integrity in transcriptionally active regions is pivotal for suppressing oncogenic mutations, yet the mechanisms that govern precise homologous recombination (HR) repair within these regions remain elusive. Here, we report that the IRAK1-spliceosome axis operates with small nuclear RNA (snRNA) as a central molecular hub, potently promoting accurate repair at DNA double-strand break (DSB) sites within active chromatin. Mechanistically, IRAK1 phosphorylates spliceosomal SR proteins to recruit snRNA to DSBs, inducing robust condensation of the MRE11-RAD50-NBS1 (MRN) complex near transcriptionally active regions to create an ATM activation platform. Inhibiting the IRAK1-spliceosome-snRNA axis impairs HR repair in transcriptionally active regions, causing a marked increase in mutation rates specific to these regions and cancer cell chemosensitivity. Collectively, our findings define a prevalent mechanism governing region-specific precise repair in transcriptionally active domains, where snRNA acts as a “transcription repair bridge” to link transcriptional processes to HR repair and ultimately preserves genomic stability in these regions.

Institutions

• Peking University

  Beijing, Beijing

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