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Mps1 dimerization and multisite interactions with Ndc80 complex enable responsive spindle assembly checkpoint signaling 被引量:1
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作者 Ping Gui Divine M.Sedzro +11 位作者 Xiao Yuan Sikai Liu Mohan Hei Wei Tian Najdat Zohbi Fangwei Wang Yihan Yao Felix O.Aikhionbare Xinjiao Gao Dongmei Wang Xuebiao Yao Zhen Dou 《Journal of Molecular Cell Biology》 SCIE CAS CSCD 2020年第7期486-498,共13页
Error-free mitosis depends on accurate chromosome attachment to spindle microtubules,which is monitored by the spindle assembly checkpoint(SAC)signaling.As an upstream factor of SAC,the precise and dynamic kinetochore... Error-free mitosis depends on accurate chromosome attachment to spindle microtubules,which is monitored by the spindle assembly checkpoint(SAC)signaling.As an upstream factor of SAC,the precise and dynamic kinetochore localization of Mps1 kinase is critical for initiating and silencing SAC signaling.However,the underlying molecular mechanism remains elusive.Here,we demonstrated that the multisite interactions between Mps1 and Ndc80 complex(Ndc80C)govern Mps1 kinetochore targeting.Importantly,we identified direct interaction between Mps1 tetratricopeptide repeat domain and Ndc80C.We further identified that Mps1 C-terminal fragment,which contains the protein kinase domain and C-tail,enhances Mps1 kinetochore localization.Mechanistically,Mps1 C-terminal fragment mediates its dimerization.Perturbation of C-tail attenuates the kinetochore targeting and activity of Mps1,leading to aberrant mitosis due to compromised SAC function.Taken together,our study highlights the importance of Mps1 dimerization and multisite interactions with Ndc80C in enabling responsive SAC signaling. 展开更多
关键词 MITOSIS spindle assembly checkpoint KINETOCHORE Mps1 kinase Ndc80 complex
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The spindle assembly checkpoint:perspectives in tumorigenesis and cancer therapy 被引量:1
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作者 Joana BARBOSA Ana Vanessa NASCIMENTO +2 位作者 Juliana FARIA Patrícia SILVA Hassan BOUSBAA 《Frontiers in Biology》 CSCD 2011年第2期147-155,共9页
Loss or gain of chromosomes,a condition known as aneuploidy,is a common feature of tumor cells and has therefore been proposed as the driving force for tumorigenesis.Such chromosomal instability can arise during mitos... Loss or gain of chromosomes,a condition known as aneuploidy,is a common feature of tumor cells and has therefore been proposed as the driving force for tumorigenesis.Such chromosomal instability can arise during mitosis as a result of mis-segregation of the duplicated sister chromatids to the two daughter cells.In normal cells,missegregation is usually prevented by the spindle assembly checkpoint(SAC),a sophisticated surveillance mechanism that inhibits mitotic exit until all chromosomes have successfully achieved bipolar attachment to spindle microtubules.Complete abrogation of SAC activity is lethal to normal as well as to tumor cells,as a consequence of massive chromosome mis-segregation.Importantly,many human aneuploid tumor cells exhibit a weakened SAC activity that allows them to tolerate gains or losses of a small number of chromosomes;and interfering with this SAC residual activity may constitute a suitable strategy to kill cancer cells.This review focuses on the potential link between SAC and tumorigenesis,and the therapeutic strategy to target the SAC for cancer treatment. 展开更多
关键词 spindle assembly checkpoint MITOSIS chromosome instability TUMOR cancer therapy
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Spatial separation of phosphatase and kinase activity within the Bub complex is required for proper mitosis
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作者 Lei Wang Thomas Kruse +8 位作者 Blanca López-Méndez Yuqing Zhang Chunlin Song Lei Zhu Bing Li Jing Fang Zhimin Lu Jakob Nilsson Gang Zhang 《Journal of Molecular Cell Biology》 SCIE CAS CSCD 2022年第11期24-35,共12页
The Bub1 and BubR1 kinetochore proteins support proper chromosome segregation and mitotic checkpoint activity. Bub1 and BubR1 are paralogs with Bub1 being a kinase, while BubR1 localizes the PP2A-B56 protein phosphata... The Bub1 and BubR1 kinetochore proteins support proper chromosome segregation and mitotic checkpoint activity. Bub1 and BubR1 are paralogs with Bub1 being a kinase, while BubR1 localizes the PP2A-B56 protein phosphatase to kinetochores in humans. Whether this spatial separation of kinase and phosphatase activity is important is unclear as some organisms integrate both activities into one Bub protein. Here, we engineer human Bub1 and BubR1 proteins integrating kinase and phosphatase activities into one protein and show that these do not support normal mitotic progression. A Bub1–PP2A-B56 complex can support chromosome alignment but results in impairment of the checkpoint due to dephosphorylation of the Mad1 binding site in Bub1. Furthermore, a chimeric BubR1 protein containing the Bub1 kinase domain induces delocalized H2ApT120 phosphorylation, resulting in the reduction of centromeric hSgo2 and chromosome segregation errors. Collectively, these results argue that the spatial separation of kinase and phosphatase activities within the Bub complex is required for balancing its functions in the checkpoint and chromosome alignment. 展开更多
关键词 MITOSIS spindle assembly checkpoint KINETOCHORES BUB1 BUBR1 PP2A/B56
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Comparative analysis of chromosome segregation in human, yeasts and trypanosome
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作者 Xianxian HAN Ziyin LI 《Frontiers in Biology》 CAS CSCD 2014年第6期472-480,共9页
Chromosome segregation is a tightly regulated process through which duplicated genetic materials are equally partitioned into daughter cells. During the past decades, tremendous efforts have been made to understand th... Chromosome segregation is a tightly regulated process through which duplicated genetic materials are equally partitioned into daughter cells. During the past decades, tremendous efforts have been made to understand the molecular mechanism of chromosome segregation using animals and yeasts as model systems. Recently, new insights into chromosome segregation have gradually emerged using trypanosome, an early branching parasitic protozoan, as a model organism. To uncover the unique aspects of chromosome segregation in trypanosome, which potentially could serve as new drug targets for anti-trypanosome chemotherapy, it is necessary to perform a comparative analysis of the chromosome segregation machinery between trypanosome and its human host. Here, we briefly review the current knowledge about chromosome segregation in human and Trypanosoma brucei, with a focus on the regulation of cohesin and securin degradation triggered by the activation of the anaphase promoting complex/cyclosome (APC/C). We also include yeasts in our comparative analysis since some of the original discoveries were made using budding and fission yeasts as the model organisms and, therefore, these could provide hints about the evolution of the machinery. We highlight both common and unique features in these model systems and also provide perspectives for future research in trypanosome. 展开更多
关键词 COHESIN SEPARASE SECURIN anaphase promoting complex spindle assembly checkpoint T^panosoma brucei
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