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Excessive reactive oxygen species induce transcription-dependent replication stress

Author

Listed:
  • Martin Andrs

    (Institute of Molecular Genetics of the Czech Academy of Sciences
    University of Zurich)

  • Henriette Stoy

    (University of Zurich)

  • Barbora Boleslavska

    (Institute of Molecular Genetics of the Czech Academy of Sciences
    Charles University in Prague)

  • Nagaraja Chappidi

    (University of Zurich
    Technische Universität Dresden)

  • Radhakrishnan Kanagaraj

    (University of Westminster
    University of Bedfordshire
    Sathyabama Institute of Science and Technology)

  • Zuzana Nascakova

    (Institute of Molecular Genetics of the Czech Academy of Sciences
    University of Zurich)

  • Shruti Menon

    (University of Zurich
    University of California San Francisco (UCSF))

  • Satyajeet Rao

    (University of Zurich)

  • Anna Oravetzova

    (Institute of Molecular Genetics of the Czech Academy of Sciences
    Charles University in Prague)

  • Jana Dobrovolna

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Kalpana Surendranath

    (University of Westminster
    Sathyabama Institute of Science and Technology)

  • Massimo Lopes

    (University of Zurich)

  • Pavel Janscak

    (Institute of Molecular Genetics of the Czech Academy of Sciences
    University of Zurich)

Abstract

Elevated levels of reactive oxygen species (ROS) reduce replication fork velocity by causing dissociation of the TIMELESS-TIPIN complex from the replisome. Here, we show that ROS generated by exposure of human cells to the ribonucleotide reductase inhibitor hydroxyurea (HU) promote replication fork reversal in a manner dependent on active transcription and formation of co-transcriptional RNA:DNA hybrids (R-loops). The frequency of R-loop-dependent fork stalling events is also increased after TIMELESS depletion or a partial inhibition of replicative DNA polymerases by aphidicolin, suggesting that this phenomenon is due to a global replication slowdown. In contrast, replication arrest caused by HU-induced depletion of deoxynucleotides does not induce fork reversal but, if allowed to persist, leads to extensive R-loop-independent DNA breakage during S-phase. Our work reveals a link between oxidative stress and transcription-replication interference that causes genomic alterations recurrently found in human cancer.

Suggested Citation

  • Martin Andrs & Henriette Stoy & Barbora Boleslavska & Nagaraja Chappidi & Radhakrishnan Kanagaraj & Zuzana Nascakova & Shruti Menon & Satyajeet Rao & Anna Oravetzova & Jana Dobrovolna & Kalpana Surend, 2023. "Excessive reactive oxygen species induce transcription-dependent replication stress," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37341-y
    DOI: 10.1038/s41467-023-37341-y
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    References listed on IDEAS

    as
    1. Sofija Mijic & Ralph Zellweger & Nagaraja Chappidi & Matteo Berti & Kurt Jacobs & Karun Mutreja & Sebastian Ursich & Arnab Ray Chaudhuri & Andre Nussenzweig & Pavel Janscak & Massimo Lopes, 2017. "Replication fork reversal triggers fork degradation in BRCA2-defective cells," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    2. Julie Rageul & Jennifer J. Park & Ping Ping Zeng & Eun-A Lee & Jihyeon Yang & Sunyoung Hwang & Natalie Lo & Alexandra S. Weinheimer & Orlando D. Schärer & Jung-Eun Yeo & Hyungjin Kim, 2020. "SDE2 integrates into the TIMELESS-TIPIN complex to protect stalled replication forks," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
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    1. Miho M. Suzuki & Kenta Iijima & Koichi Ogami & Keiko Shinjo & Yoshiteru Murofushi & Jingqi Xie & Xuebing Wang & Yotaro Kitano & Akira Mamiya & Yuji Kibe & Tatsunori Nishimura & Fumiharu Ohka & Ryuta S, 2023. "TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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