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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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    1. Aparna Gorthi & July Carolina Romero & Eva Loranc & Lin Cao & Liesl A. Lawrence & Elicia Goodale & Amanda Balboni Iniguez & Xavier Bernard & V. Pragathi Masamsetti & Sydney Roston & Elizabeth R. Lawlo, 2018. "Author Correction: EWS–FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma," Nature, Nature, vol. 559(7715), pages 11-11, July.
    2. Pedro Ortega & Belén Gómez-González & Andrés Aguilera, 2019. "Rpd3L and Hda1 histone deacetylases facilitate repair of broken forks by promoting sister chromatid cohesion," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    3. Lisa Prendergast & Urszula L. McClurg & Rossitsa Hristova & Rolando Berlinguer-Palmini & Sarah Greener & Katie Veitch & Inmaculada Hernandez & Philippe Pasero & Daniel Rico & Jonathan M. G. Higgins & , 2020. "Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    4. Yentram Huyen & Omar Zgheib & Richard A. DiTullio Jr & Vassilis G. Gorgoulis & Panayotis Zacharatos & Tom J. Petty & Emily A. Sheston & Hestia S. Mellert & Elena S. Stavridi & Thanos D. Halazonetis, 2004. "Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks," Nature, Nature, vol. 432(7015), pages 406-411, November.
    5. Aparna Gorthi & July Carolina Romero & Eva Loranc & Lin Cao & Liesl A. Lawrence & Elicia Goodale & Amanda Balboni Iniguez & Xavier Bernard & V. Pragathi Masamsetti & Sydney Roston & Elizabeth R. Lawlo, 2018. "EWS–FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma," Nature, Nature, vol. 555(7696), pages 387-391, March.
    6. Vaibhav Bhatia & Sonia I. Barroso & María L. García-Rubio & Emanuela Tumini & Emilia Herrera-Moyano & Andrés Aguilera, 2014. "BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2," Nature, Nature, vol. 511(7509), pages 362-365, July.
    7. Konstantina Skourti-Stathaki & Kinga Kamieniarz-Gdula & Nicholas J. Proudfoot, 2014. "R-loops induce repressive chromatin marks over mammalian gene terminators," Nature, Nature, vol. 516(7531), pages 436-439, December.
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