IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42653-0.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42653-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-42653-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yan Wang & Binbin Ma & Xiaoxu Liu & Ge Gao & Zhuanzhuan Che & Menghan Fan & Siyan Meng & Xiru Zhao & Rio Sugimura & Hua Cao & Zhongjun Zhou & Jing Xie & Chengqi Lin & Zhuojuan Luo, 2022. "ZFP281-BRCA2 prevents R-loop accumulation during DNA replication," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Heathcliff Dorado García & Fabian Pusch & Yi Bei & Jennifer Stebut & Glorymar Ibáñez & Kristina Guillan & Koshi Imami & Dennis Gürgen & Jana Rolff & Konstantin Helmsauer & Stephanie Meyer-Liesener & N, 2022. "Therapeutic targeting of ATR in alveolar rhabdomyosarcoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Haibo Yang & Emily M. Lachtara & Xiaojuan Ran & Jessica Hopkins & Parasvi S. Patel & Xueping Zhu & Yao Xiao & Laiyee Phoon & Boya Gao & Lee Zou & Michael S. Lawrence & Li Lan, 2023. "The RNA m5C modification in R-loops as an off switch of Alt-NHEJ," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Arun Prakash Mishra & Suzanne A. Hartford & Sounak Sahu & Kimberly Klarmann & Rajani Kant Chittela & Kajal Biswas & Albert B. Jeon & Betty K. Martin & Sandra Burkett & Eileen Southon & Susan Reid & Ma, 2022. "BRCA2-DSS1 interaction is dispensable for RAD51 recruitment at replication-induced and meiotic DNA double strand breaks," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Uta Eberlein & Michel Peper & Maria Fernández & Michael Lassmann & Harry Scherthan, 2015. "Calibration of the γ-H2AX DNA Double Strand Break Focus Assay for Internal Radiation Exposure of Blood Lymphocytes," PLOS ONE, Public Library of Science, vol. 10(4), pages 1-11, April.
    6. Liang Chen & Yucong Wang & Jiamei Lin & Zhenxing Song & Qinwei Wang & Wenfang Zhao & Yan Wang & Xiaoyu Xiu & Yuqi Deng & Xiuzhi Li & Qiqi Li & Xiaolin Wang & Jingxin Li & Xu Liu & Kunpeng Liu & Jincon, 2022. "Exportin 4 depletion leads to nuclear accumulation of a subset of circular RNAs," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. David Rombaut & Carine Lefèvre & Tony Rached & Sabrina Bondu & Anne Letessier & Raphael M. Mangione & Batoul Farhat & Auriane Lesieur-Pasquier & Daisy Castillo-Guzman & Ismael Boussaid & Chloé Friedri, 2024. "Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42653-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.