In mitosis,accurate chromosome segregation depends on the kinetochore,a supermolecular machinery that couples dynamic spin-dle microtubules to centromeric chromatin.However,the structure–activity relationship of the ...In mitosis,accurate chromosome segregation depends on the kinetochore,a supermolecular machinery that couples dynamic spin-dle microtubules to centromeric chromatin.However,the structure–activity relationship of the constitutive centromere-associated network(CCAN)during mitosis remains uncharacterized.Building on our recent cryo-electron microscopic analyses of human CCAN structure,we investigated how dynamic phosphorylation of human CENP-N regulates accurate chromosome segregation.Our mass spectrometric analyses revealed mitotic phosphorylation of CENP-N by CDK1,which modulates the CENP-L–CENP-N interaction for accurate chromosome segregation and CCAN organization.Perturbation of CENP-N phosphorylation is shown to prevent proper chromosome alignment and activate the spindle assembly checkpoint.These analyses provide mechanistic insight into a previously undefined link between the centromere–kinetochore network and accurate chromosome segregation.展开更多
Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation.In eukaryotic cells,nuclear envelope breakdown(NEBD)is required for proper chromoso...Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation.In eukaryotic cells,nuclear envelope breakdown(NEBD)is required for proper chromosome segregation.Although a list of mitotic kinases has been implicated in NEBD,how they coordinate their activity to dissolve the nuclear envelope and protein machinery such as nuclear pore complexes was unclear.Here,we identified a regulatory mechanism in which Nup62 is acetylated by TIP60 in human cell division.Nup62 is a novel substrate of TIP60,and the acetylation of Lys432 by TIP60 dissolves nucleoporin Nup62-Nup58-Nup54 complex during entry into mitosis.Importantly,this acetylation-elicited remodeling of nucleoporin complex promotes the distribution of Nup62 to the mitotic spindle,which is indispensable for orchestrating correct spindle orientation.Moreover,suppression of Nup62 perturbs accurate chromosome segregation during mitosis.These results establish a previously uncharacterized regulatory mechanism in which TIP60-elicited nucleoporin dynamics promotes chromosome segregation in mitosis.展开更多
基金supported by grants from the Ministry of Science and Technology of the People’s Republic of China and the National Natural Science Foundation of China(2022YFA1303100,2022YFA0806800,92153302,32090040,92254302,21922706,91853115 to X.L.,2017YFA0503600,31621002,U1532109,91853133 to J.Z.,32170733,2017YFA0102900,31871359 to Z.D.,32000858 to T.T.)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB37010105 to J.Z.and XDB19040000 to X.L.)+3 种基金the Ministry of Education(IRT_17R102,20113402130010,YD2070006001 to X.L.)Anhui Provincial Natural Science Foundation(2108085J15 to Z.D.,2008085QC145 to T.T.)the Fundamental Research Funds for the Central Universities(WK2070000171 to T.T.)the University of Science and Technology of China Research Funds of the Double First-Class Initiative(YD2070002015 to X.Z.)。
文摘In mitosis,accurate chromosome segregation depends on the kinetochore,a supermolecular machinery that couples dynamic spin-dle microtubules to centromeric chromatin.However,the structure–activity relationship of the constitutive centromere-associated network(CCAN)during mitosis remains uncharacterized.Building on our recent cryo-electron microscopic analyses of human CCAN structure,we investigated how dynamic phosphorylation of human CENP-N regulates accurate chromosome segregation.Our mass spectrometric analyses revealed mitotic phosphorylation of CENP-N by CDK1,which modulates the CENP-L–CENP-N interaction for accurate chromosome segregation and CCAN organization.Perturbation of CENP-N phosphorylation is shown to prevent proper chromosome alignment and activate the spindle assembly checkpoint.These analyses provide mechanistic insight into a previously undefined link between the centromere–kinetochore network and accurate chromosome segregation.
基金supported by grants from the National Key Re-search and Development Program of China(2017YFA0503600 and 2016YFA0100500)the National Natural Science Founda-tion of China(31621002,32090040,91854203,21922706,91853115,92153302,22177106,92053104,31970655,and 32100612)+2 种基金the Ministry of Education(IRT_17R102),Anhui Provincial Natural Science Foundation(2108085J15)the Strate-gic Priority Research Program of the Chinese Academy of Sci-ences(XDB19040000)the Fundamental Research Funds for the Central Universities(WK2070000066 and WK2070000194).
文摘Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation.In eukaryotic cells,nuclear envelope breakdown(NEBD)is required for proper chromosome segregation.Although a list of mitotic kinases has been implicated in NEBD,how they coordinate their activity to dissolve the nuclear envelope and protein machinery such as nuclear pore complexes was unclear.Here,we identified a regulatory mechanism in which Nup62 is acetylated by TIP60 in human cell division.Nup62 is a novel substrate of TIP60,and the acetylation of Lys432 by TIP60 dissolves nucleoporin Nup62-Nup58-Nup54 complex during entry into mitosis.Importantly,this acetylation-elicited remodeling of nucleoporin complex promotes the distribution of Nup62 to the mitotic spindle,which is indispensable for orchestrating correct spindle orientation.Moreover,suppression of Nup62 perturbs accurate chromosome segregation during mitosis.These results establish a previously uncharacterized regulatory mechanism in which TIP60-elicited nucleoporin dynamics promotes chromosome segregation in mitosis.
