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The Bloom syndrome complex senses RPA-coated single-stranded DNA to restart stalled replication forks

Author

Listed:
  • Ann-Marie K. Shorrocks

    (University of Oxford, John Radcliffe Hospital
    Department of Oncology, University of Oxford)

  • Samuel E. Jones

    (University of Oxford, John Radcliffe Hospital
    Department of Oncology, University of Oxford)

  • Kaima Tsukada

    (University of Oxford, John Radcliffe Hospital
    Department of Oncology, University of Oxford
    School of Environment and Society, Tokyo Institute of Technology)

  • Carl A. Morrow

    (University of Oxford, John Radcliffe Hospital
    Department of Oncology, University of Oxford)

  • Zoulikha Belblidia

    (University of Oxford, John Radcliffe Hospital
    Department of Oncology, University of Oxford)

  • Johanna Shen

    (University of Oxford, John Radcliffe Hospital
    Department of Oncology, University of Oxford
    Yale University)

  • Iolanda Vendrell

    (Department of Oncology, University of Oxford
    University of Oxford)

  • Roman Fischer

    (University of Oxford)

  • Benedikt M. Kessler

    (University of Oxford)

  • Andrew N. Blackford

    (University of Oxford, John Radcliffe Hospital
    Department of Oncology, University of Oxford)

Abstract

The Bloom syndrome helicase BLM interacts with topoisomerase IIIα (TOP3A), RMI1 and RMI2 to form the BTR complex, which dissolves double Holliday junctions to produce non-crossover homologous recombination (HR) products. BLM also promotes DNA-end resection, restart of stalled replication forks, and processing of ultra-fine DNA bridges in mitosis. How these activities of the BTR complex are regulated in cells is still unclear. Here, we identify multiple conserved motifs within the BTR complex that interact cooperatively with the single-stranded DNA (ssDNA)-binding protein RPA. Furthermore, we demonstrate that RPA-binding is required for stable BLM recruitment to sites of DNA replication stress and for fork restart, but not for its roles in HR or mitosis. Our findings suggest a model in which the BTR complex contains the intrinsic ability to sense levels of RPA-ssDNA at replication forks, which controls BLM recruitment and activation in response to replication stress.

Suggested Citation

  • Ann-Marie K. Shorrocks & Samuel E. Jones & Kaima Tsukada & Carl A. Morrow & Zoulikha Belblidia & Johanna Shen & Iolanda Vendrell & Roman Fischer & Benedikt M. Kessler & Andrew N. Blackford, 2021. "The Bloom syndrome complex senses RPA-coated single-stranded DNA to restart stalled replication forks," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20818-5
    DOI: 10.1038/s41467-020-20818-5
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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. S. Cohen & A. Guenolé & I. Lazar & A. Marnef & T. Clouaire & D. V. Vernekar & N. Puget & V. Rocher & C. Arnould & M. Aguirrebengoa & M. Genais & N. Firmin & R. A. Shamanna & R. Mourad & V. A. Bohr & V, 2022. "A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Chaoyou Xue & Sameer J. Salunkhe & Nozomi Tomimatsu & Ajinkya S. Kawale & Youngho Kwon & Sandeep Burma & Patrick Sung & Eric C. Greene, 2022. "Bloom helicase mediates formation of large single–stranded DNA loops during DNA end processing," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Liton Kumar Saha & Sourav Saha & Xi Yang & Shar-yin Naomi Huang & Yilun Sun & Ukhyun Jo & Yves Pommier, 2023. "Replication-associated formation and repair of human topoisomerase IIIα cleavage complexes," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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