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

ABSTRACT: The BTRR (BLM/TOP3A/RMI1/RMI2) complex resolves various DNA replication and recombination intermediates to suppress genome instability. 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, multiple protein kinases act together to strictly constrain the BTRR complex for the protection of centromeres. Mechanistically, CDK1 destabilises the complex and suppresses its association with PICH at the chromatin underneath kinetochores. Inactivating the BLM and TOP3A interaction compromises the UFB-binding complex mitotic functions and can prevent centromere destruction. We further unravel how different clusters of mitotic phosphorylation on BLM affect its interaction with the TOP3A/RMI1/RMI2 subcomplex and illegitimate centromere unwinding. Furthermore, we identify specific phosphorylation sites targeted by the MPS1-PLK1 axis functioning to prevent BLM hyper-activation at centromeres. Notably, unleashing such activity after sister-chromatid cohesion loss facilitates separation of entangled chromosomes. Together, our study defines a centromere protection pathway in human mitotic cells, heavily reliant on a tight spatiotemporal control of the BTRR complex.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Umit Aliyaskarova

LAB HEAD: Kok-Lung Chan

PROVIDER: PXD052669 | Pride | 2025-08-12

REPOSITORIES: Pride

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			Action	DRS
	F026954.csv	Csv
	F026954.mgf	Mgf
	F026954.mzid.gz	Mzid
	F026954.wiff	Wiff
	F026954.wiff.scan	Wiff

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

Project description:The BTRR (BLM/TOP3A/RMI1/RMI2) complex resolves various DNA replication and recombination intermediates to suppress genome instability. 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, multiple protein kinases act together to strictly constrain the BTRR complex for the protection of centromeres. Mechanistically, CDK1 destabilises the complex and suppresses its association with PICH at the chromatin underneath kinetochores. Inactivating the BLM and TOP3A interaction compromises the UFB-binding complex mitotic functions and can prevent centromere destruction. We further unravel how different clusters of mitotic phosphorylation on BLM affect its interaction with the TOP3A/RMI1/RMI2 subcomplex and illegitimate centromere unwinding. Furthermore, we identify specific phosphorylation sites targeted by the MPS1-PLK1 axis functioning to prevent BLM hyper-activation at centromeres. Notably, unleashing such activity after sister-chromatid cohesion loss facilitates separation of entangled chromosomes. Together, our study defines a centromere protection pathway in human mitotic cells, heavily reliant on a tight spatiotemporal control of the BTRR complex.

2025-08-27 | PXD052850 | Pride

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

Project description:The BTRR (BLM/TOP3A/RMI1/RMI2) complex resolves various DNA replication and recombination intermediates to suppress genome instability. 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, multiple protein kinases act together to strictly constrain BTRR complex activities at centromeres. Mechanistically, CDK1 destabilises the complex and suppresses its association with PICH at the chromatin underneath kinetochores. Inactivating the BLM and TOP3A interaction compromises the UFB-binding complex mitotic functions and can prevent centromere destruction. We further unravel how different mitotic phosphorylation sites of BLM affect its interaction with the TOP3A/RMI1/RMI2 subcomplex and centromeric DNA unwinding. Furthermore, we show that multiple PLK1-mediated phosphorylation on BLM is required to suppress aberrant centromere unwinding. However, notably, unleashing such activity after sister-chromatid cohesion loss facilitates separation of entangled chromosomes. Together, our study defines a centromere protection pathway in human mitotic cells, heavily reliant on a tight spatiotemporal control of the BTRR complex.

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