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

María Fernández-Casañas, Eleftheria Karanika, Umit Aliyaskarova, Tomisin Olukoga, Alex D. Herbert, Antony W. Oliver, Matthew Day, Adrijana Crncec and Kok-Lung Chan ()
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María Fernández-Casañas: University of Sussex
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
Kok-Lung Chan: University of Sussex

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62966-6

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