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The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts

Author

Listed:
  • Aleix Bayona-Feliu

    (Universidad de Sevilla-CSIC-Universidad Pablo de Olavide
    Universidad de Sevilla
    The Barcelona Institute of Science and Technology (BIST))

  • Emilia Herrera-Moyano

    (Universidad de Sevilla-CSIC-Universidad Pablo de Olavide
    Universidad de Sevilla)

  • Nibal Badra-Fajardo

    (Universidad de Sevilla-CSIC-Universidad Pablo de Olavide)

  • Iván Galván-Femenía

    (The Barcelona Institute of Science and Technology (BIST))

  • María Eugenia Soler-Oliva

    (Universidad de Sevilla-CSIC-Universidad Pablo de Olavide
    Universidad de Sevilla)

  • Andrés Aguilera

    (Universidad de Sevilla-CSIC-Universidad Pablo de Olavide
    Universidad de Sevilla)

Abstract

Genome instability is a feature of cancer cells, transcription being an important source of DNA damage. This is in large part associated with R-loops, which hamper replication, especially at head-on transcription-replication conflicts (TRCs). Here we show that TRCs trigger a DNA Damage Response (DDR) involving the chromatin network to prevent genome instability. Depletion of the key chromatin factors INO80, SMARCA5 and MTA2 results in TRCs, fork stalling and R-loop-mediated DNA damage which mostly accumulates at S/G2, while histone H3 Ser10 phosphorylation, a mark of chromatin compaction, is enriched at TRCs. Strikingly, TRC regions show increased mutagenesis in cancer cells with signatures of homologous recombination deficiency, transcription-coupled nucleotide excision repair (TC-NER) and of the AID/APOBEC cytidine deaminases, being predominant at head-on collisions. Thus, our results support that the chromatin network prevents R-loops and TRCs from genomic instability and mutagenic signatures frequently associated with cancer.

Suggested Citation

  • Aleix Bayona-Feliu & Emilia Herrera-Moyano & Nibal Badra-Fajardo & Iván Galván-Femenía & María Eugenia Soler-Oliva & Andrés Aguilera, 2023. "The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42653-0
    DOI: 10.1038/s41467-023-42653-0
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    References listed on IDEAS

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