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RPA shields inherited DNA lesions for post-mitotic DNA synthesis

Author

Listed:
  • Aleksandra Lezaja

    (University of Zurich)

  • Andreas Panagopoulos

    (University of Zurich)

  • Yanlin Wen

    (University of Zurich)

  • Edison Carvalho

    (University of Zurich)

  • Ralph Imhof

    (University of Zurich)

  • Matthias Altmeyer

    (University of Zurich)

Abstract

The paradigm that checkpoints halt cell cycle progression for genome repair has been challenged by the recent discovery of heritable DNA lesions escaping checkpoint control. How such inherited lesions affect genome function and integrity is not well understood. Here, we identify a new class of heritable DNA lesions, which is marked by replication protein A (RPA), a protein primarily known for shielding single-stranded DNA in S/G2. We demonstrate that post-mitotic RPA foci occur at low frequency during unperturbed cell cycle progression, originate from the previous cell cycle, and are exacerbated upon replication stress. RPA-marked inherited ssDNA lesions are found at telomeres, particularly of ALT-positive cancer cells. We reveal that RPA protects these replication remnants in G1 to allow for post-mitotic DNA synthesis (post-MiDAS). Given that ALT-positive cancer cells exhibit high levels of replication stress and telomere fragility, targeting post-MiDAS might be a new therapeutic opportunity.

Suggested Citation

  • Aleksandra Lezaja & Andreas Panagopoulos & Yanlin Wen & Edison Carvalho & Ralph Imhof & Matthias Altmeyer, 2021. "RPA shields inherited DNA lesions for post-mitotic DNA synthesis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23806-5
    DOI: 10.1038/s41467-021-23806-5
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    Cited by:

    1. Poonam Roshan & Sahiti Kuppa & Jenna R. Mattice & Vikas Kaushik & Rahul Chadda & Nilisha Pokhrel & Brunda R. Tumala & Aparna Biswas & Brian Bothner & Edwin Antony & Sofia Origanti, 2023. "An Aurora B-RPA signaling axis secures chromosome segregation fidelity," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Nina Schmolka & Ino D. Karemaker & Richard Cardoso da Silva & Davide C. Recchia & Vincent Spegg & Jahnavi Bhaskaran & Michael Teske & Nathalie P. Wagenaar & Matthias Altmeyer & Tuncay Baubec, 2023. "Dissecting the roles of MBD2 isoforms and domains in regulating NuRD complex function during cellular differentiation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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