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High speed of fork progression induces DNA replication stress and genomic instability

Author

Listed:
  • Apolinar Maya-Mendoza

    (Genome Integrity Unit, Danish Cancer Society Research Center)

  • Pavel Moudry

    (Genome Integrity Unit, Danish Cancer Society Research Center
    Palacky University)

  • Joanna Maria Merchut-Maya

    (Genome Integrity Unit, Danish Cancer Society Research Center)

  • MyungHee Lee

    (Genome Integrity Unit, Danish Cancer Society Research Center)

  • Robert Strauss

    (Genome Integrity Unit, Danish Cancer Society Research Center)

  • Jiri Bartek

    (Genome Integrity Unit, Danish Cancer Society Research Center
    Palacky University
    Karolinska Institute)

Abstract

Accurate replication of DNA requires stringent regulation to ensure genome integrity. In human cells, thousands of origins of replication are coordinately activated during S phase, and the velocity of replication forks is adjusted to fully replicate DNA in pace with the cell cycle1. Replication stress induces fork stalling and fuels genome instability2. The mechanistic basis of replication stress remains poorly understood despite its emerging role in promoting cancer2. Here we show that inhibition of poly(ADP-ribose) polymerase (PARP) increases the speed of fork elongation and does not cause fork stalling, which is in contrast to the accepted model in which inhibitors of PARP induce fork stalling and collapse3. Aberrant acceleration of fork progression by 40% above the normal velocity leads to DNA damage. Depletion of the treslin or MTBP proteins, which are involved in origin firing, also increases fork speed above the tolerated threshold, and induces the DNA damage response pathway. Mechanistically, we show that poly(ADP-ribosyl)ation (PARylation) and the PCNA interactor p21Cip1 (p21) are crucial modulators of fork progression. PARylation and p21 act as suppressors of fork speed in a coordinated regulatory network that is orchestrated by the PARP1 and p53 proteins. Moreover, at the fork level, PARylation acts as a sensor of replication stress. During PARP inhibition, DNA lesions that induce fork arrest and are normally resolved or repaired remain unrecognized by the replication machinery. Conceptually, our results show that accelerated replication fork progression represents a general mechanism that triggers replication stress and the DNA damage response. Our findings contribute to a better understanding of the mechanism of fork speed control, with implications for genomic (in)stability and rational cancer treatment.

Suggested Citation

  • Apolinar Maya-Mendoza & Pavel Moudry & Joanna Maria Merchut-Maya & MyungHee Lee & Robert Strauss & Jiri Bartek, 2018. "High speed of fork progression induces DNA replication stress and genomic instability," Nature, Nature, vol. 559(7713), pages 279-284, July.
  • Handle: RePEc:nat:nature:v:559:y:2018:i:7713:d:10.1038_s41586-018-0261-5
    DOI: 10.1038/s41586-018-0261-5
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    Cited by:

    1. Vanessa Rousseau & Elias Einig & Chao Jin & Julia Horn & Mathias Riebold & Tanja Poth & Mohamed-Ali Jarboui & Michael Flentje & Nikita Popov, 2023. "Trim33 masks a non-transcriptional function of E2f4 in replication fork progression," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Anne Margriet Heijink & Colin Stok & David Porubsky & Eleni Maria Manolika & Jurrian K. Kanter & Yannick P. Kok & Marieke Everts & H. Rudolf Boer & Anastasia Audrey & Femke J. Bakker & Elles Wierenga , 2022. "Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Anchel de Jaime-Soguero & Janina Hattemer & Anja Bufe & Alexander Haas & Jeroen Berg & Vincent Batenburg & Biswajit Das & Barbara Marco & Stefania Androulaki & Nicolas Böhly & Jonathan J. M. Landry & , 2024. "Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    4. Megan E. Luedeman & Susanna Stroik & Wanjuan Feng & Adam J. Luthman & Gaorav P. Gupta & Dale A. Ramsden, 2022. "Poly(ADP) ribose polymerase promotes DNA polymerase theta-mediated end joining by activation of end resection," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    5. 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.
    6. Maria Dilia Palumbieri & Chiara Merigliano & Daniel González-Acosta & Danina Kuster & Jana Krietsch & Henriette Stoy & Thomas Känel & Svenja Ulferts & Bettina Welter & Joël Frey & Cyril Doerdelmann & , 2023. "Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. Ke Cong & Nathan MacGilvary & Silviana Lee & Shannon G. MacLeod & Jennifer Calvo & Min Peng & Arne Nedergaard Kousholt & Tovah A. Day & Sharon B. Cantor, 2024. "FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    8. Zuzana Machacova & Katarina Chroma & David Lukac & Iva Protivankova & Pavel Moudry, 2024. "DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    9. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    10. Liana Goehring & Sarah Keegan & Sudipta Lahiri & Wenxin Xia & Michael Kong & Judit Jimenez-Sainz & Dipika Gupta & Ronny Drapkin & Ryan B. Jensen & Duncan J. Smith & Eli Rothenberg & David Fenyö & Tony, 2024. "Dormant origin firing promotes head-on transcription-replication conflicts at transcription termination sites in response to BRCA2 deficiency," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    11. Cuige Zhu & Mari Iwase & Ziqian Li & Faliang Wang & Annabel Quinet & Alessandro Vindigni & Jieya Shao, 2022. "Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    12. Domagoj Vugic & Isaac Dumoulin & Charlotte Martin & Anna Minello & Lucia Alvaro-Aranda & Jesus Gomez-Escudero & Rady Chaaban & Rana Lebdy & Catharina Nicolai & Virginie Boucherit & Cyril Ribeyre & Ang, 2023. "Replication gap suppression depends on the double-strand DNA binding activity of BRCA2," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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