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NONO mitigates transcription-replication conflicts during replication stress by restraining BRD4-dependent transcription elongation

ABSTRACT: Transcription–replication conflicts (TRCs) are key drivers of genomic instability and are closely linked to tumorigenesis and treatment response. Replication stress exacerbates TRCs by inducing dormant origin firing and replication fork stalling, yet the mechanisms by which cells coordinate transcription and replication to limit these conflicts remain unclear. Here, we identify NONO as a critical regulator that maintains this balance through its interaction with BRD4. Mechanistically, replication stress induces acetylation of NONO at K243, enhancing its association with BRD4. In the presence of single-stranded DNA, NONO and BRD4 form inhibitory condensates that restrain BRD4-mediated release of promoter-proximal paused RNA polymerase II (RNAP2), thereby fine-tuning transcriptional elongation under replication stress. Loss of NONO leads to aberrant accumulation of elongating RNAP2 at transcription termination regions, promoting head-on collisions with replication machinery and resulting in genomic instability. Conditions that increase origin firing, including ATR inhibition or BRCA2 deficiency, further exacerbate this phenotype in NONO-deficient cells, leading to pronounced synthetic lethality. Together, these findings define a NONO-mediated surveillance mechanism that couples replication stress to transcriptional restraint via condensate-dependent regulation of BRD4, and identify NONO as a potential therapeutic target in replication stress–driven cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327381 | GEO | 2026/09/29

REPOSITORIES: GEO

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