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Centromere protection requires strict mitotic inactivation of the Bloom syndrome helicase complex

Author

Listed:
  • María Fernández-Casañas

    (University of Sussex
    The Institute of Cancer Research)

  • Eleftheria Karanika

    (University of Sussex)

  • Umit Aliyaskarova

    (University of Sussex)

  • Tomisin Olukoga

    (University of Sussex)

  • Alex D. Herbert

    (University of Sussex)

  • Antony W. Oliver

    (University of Sussex)

  • Matthew Day

    (Queen Mary University of London)

  • Adrijana Crncec

    (University of Sussex
    National Cancer Institute)

  • Kok-Lung Chan

    (University of Sussex)

Abstract

The BTRR (BLM/TOP3A/RMI1/RMI2) complex resolves DNA replication and recombination intermediates to maintain genome stability. Alongside PICH, they target mitotic DNA intertwinements, known as ultrafine DNA bridges, facilitating chromosome segregation. Both BLM and PICH undergo transient mitotic hyper-phosphorylation, but the biological significance of this remains elusive. Here, we uncover that during early mitosis, CDK1 and PLK1 constrain BTRR complex activities at centromeres. CDK1 destabilises the complex, limiting its binding to PICH at specialised chromatin underneath kinetochores. Inactivating the BLM-TOP3A interaction compromises the UFB-binding complex functions and prevents centromere destruction. Different phosphorylation on BLM affects the TRR subcomplex interaction and the mitotic activity, particularly phosphorylation at Ser144 and multiple PLK1-target sites suppresses illegitimate centromeric DNA unwinding. However, unleashing such activity after sister-chromatid cohesion inactivation facilitates the separation of entangled chromosomes. Here, we show a centromere protection pathway in human mitotic cells, heavily reliant on a tight spatiotemporal control of the BTRR complex.

Suggested Citation

  • María Fernández-Casañas & Eleftheria Karanika & Umit Aliyaskarova & Tomisin Olukoga & Alex D. Herbert & Antony W. Oliver & Matthew Day & Adrijana Crncec & Kok-Lung Chan, 2025. "Centromere protection requires strict mitotic inactivation of the Bloom syndrome helicase complex," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62966-6
    DOI: 10.1038/s41467-025-62966-6
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    References listed on IDEAS

    as
    1. 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.
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    4. Ankana Tiwari & Owen Addis Jones & Kok-Lung Chan, 2018. "53BP1 can limit sister-chromatid rupture and rearrangements driven by a distinct ultrafine DNA bridging-breakage process," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
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