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酵母中心体作为组织中心,促进Polo激酶介导的对持续性DNA损伤的适应性反应。

Yeast centrosomes act as organizing centers to promote Polo kinase-mediated adaptation to persistent DNA damage.

作者信息

Langlois-Lemay Laurence, D'Amours Damien

机构信息

Ottawa Institute of Systems Biology, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.

出版信息

Proc Natl Acad Sci U S A. 2025 Jul 8;122(27):e2414426122. doi: 10.1073/pnas.2414426122. Epub 2025 Jul 2.

Abstract

The ability of cells to overcome cell cycle arrest and adapt to the presence of unrepairable DNA damage is under the control of Polo-like kinases (PLKs) in eukaryotes. How DNA damage checkpoints are silenced or bypassed during the adaptation response is unknown, but the process requires enrichment of the Cdc5 PLK to microtubule organizing centers (MTOCs), such as the yeast centrosomes or spindle pole bodies (SPBs). Here, we found that SPBs play an active role as supramolecular organizing centers that coordinate Cdc5 recruitment and signaling to downstream effectors during the adaptation response to DNA damage. We show that SPB components Nud1, Spc110, and Spc72 are key effectors of Cdc5 recruitment to SPBs in the presence of sustained DNA damage. Following recruitment, Cdc5 transduces a phospho-signal to key structural subunits of the SPB, including Cnm67 and Mps3. We demonstrate these phosphorylation events are required to bypass cell cycle checkpoint arrest and enable effective adaptation to DNA damage. This response is specific because it cannot be recapitulated by a generic inactivation of MTOC activity. Collectively, our results indicate that centrosomes can act as supramolecular platforms to coordinate dynamic recruitment and substrate selection of PLKs during the DNA damage response (DDR).

摘要

在真核生物中,细胞克服细胞周期停滞并适应不可修复的DNA损伤的能力受Polo样激酶(PLK)的调控。在适应性反应过程中,DNA损伤检查点是如何被沉默或绕过的尚不清楚,但这一过程需要将Cdc5 PLK富集到微管组织中心(MTOC),如酵母中心体或纺锤极体(SPB)。在这里,我们发现SPB作为超分子组织中心发挥着积极作用,在对DNA损伤的适应性反应中协调Cdc5的招募及其向下游效应器的信号传导。我们表明,在持续存在DNA损伤的情况下,SPB组分Nud1、Spc110和Spc72是Cdc5招募到SPB的关键效应器。招募后,Cdc5将磷酸信号传递给SPB的关键结构亚基,包括Cnm67和Mps3。我们证明这些磷酸化事件是绕过细胞周期检查点停滞并有效适应DNA损伤所必需的。这种反应是特异性的,因为它不能通过MTOC活性的一般性失活来重现。总的来说,我们的结果表明,中心体可以作为超分子平台,在DNA损伤反应(DDR)过程中协调PLK的动态招募和底物选择。

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本文引用的文献

1
The dark side of PLK1: Implications for cancer and genomic instability.
Oncotarget. 2023 Jun 27;14:657-659. doi: 10.18632/oncotarget.28456.
2
Multiple Roles of PLK1 in Mitosis and Meiosis.
Cells. 2023 Jan 2;12(1):187. doi: 10.3390/cells12010187.
3
The optimal strategy balancing risk and speed predicts DNA damage checkpoint override times.
Nat Phys. 2022 Jul;18:832-839. doi: 10.1038/s41567-022-01601-3. Epub 2022 May 12.
4
DNA damage checkpoint execution and the rules of its disengagement.
Front Cell Dev Biol. 2022 Oct 6;10:1020643. doi: 10.3389/fcell.2022.1020643. eCollection 2022.
5
6
The DNA damage checkpoint: A tale from budding yeast.
Front Genet. 2022 Sep 15;13:995163. doi: 10.3389/fgene.2022.995163. eCollection 2022.
7
Moonlighting at the Poles: Non-Canonical Functions of Centrosomes.
Front Cell Dev Biol. 2022 Jul 14;10:930355. doi: 10.3389/fcell.2022.930355. eCollection 2022.
8
Present and Future Perspective on PLK1 Inhibition in Cancer Treatment.
Front Oncol. 2022 Jun 2;12:903016. doi: 10.3389/fonc.2022.903016. eCollection 2022.

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