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TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells

Author

Listed:
  • Shaun Scaramuzza

    (University of Birmingham
    Manchester Cancer Research Centre)

  • Rebecca M. Jones

    (University of Birmingham)

  • Martina Muste Sadurni

    (University of Birmingham)

  • Alicja Reynolds-Winczura

    (University of Birmingham)

  • Divyasree Poovathumkadavil

    (University of Birmingham)

  • Abigail Farrell

    (University of Birmingham)

  • Toyoaki Natsume

    (Research Organization of Information and Systems
    The Graduate University for Advanced Studies (SOKENDAI)
    Tokyo Metropolitan Institute of Medical Science)

  • Patricia Rojas

    (University of Birmingham)

  • Cyntia Fernandez Cuesta

    (University of Birmingham)

  • Masato T. Kanemaki

    (Research Organization of Information and Systems
    The Graduate University for Advanced Studies (SOKENDAI))

  • Marco Saponaro

    (University of Birmingham)

  • Agnieszka Gambus

    (University of Birmingham)

Abstract

Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication stress) is a major cause of cancer, premature aging and a spectrum of other human disorders. Over the years, TRAIP E3 ubiquitin ligase has been shown to play a role in various cellular processes that govern genome integrity and faultless segregation. TRAIP is essential for cell viability, and mutations in TRAIP ubiquitin ligase activity lead to primordial dwarfism in patients. Here, we have determined the mechanism of inhibition of cell proliferation in TRAIP-depleted cells. We have taken advantage of the auxin induced degron system to rapidly degrade TRAIP within cells and to dissect the importance of various functions of TRAIP in different stages of the cell cycle. We conclude that upon rapid TRAIP degradation, specifically in S-phase, cells cease to proliferate, arrest in G2 stage of the cell cycle and undergo senescence. Our findings reveal that TRAIP works in S-phase to prevent DNA damage at transcription start sites, caused by replication-transcription conflicts.

Suggested Citation

  • Shaun Scaramuzza & Rebecca M. Jones & Martina Muste Sadurni & Alicja Reynolds-Winczura & Divyasree Poovathumkadavil & Abigail Farrell & Toyoaki Natsume & Patricia Rojas & Cyntia Fernandez Cuesta & Mas, 2023. "TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40695-y
    DOI: 10.1038/s41467-023-40695-y
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    References listed on IDEAS

    as
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    3. Morgane Macheret & Thanos D. Halazonetis, 2018. "Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress," Nature, Nature, vol. 555(7694), pages 112-116, March.
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