title: ASPP1/2-PP1 complexes are required for chromosome segregation and kinetochore-microtubule attachments.
abstract: Regulated interactions between kinetochores and spindle microtubules are critical for maintaining genomic stability during chromosome segregation. Defects in chromosome segregation are widespread phenomenon in human cancers that are thought to serve as the fuel for tumorigenic progression. Tumor suppressor proteins ASPP1 and ASPP2, two members of the apoptosis stimulating proteins of p53 (ASPP) family, are frequently down-regulated in human cancers. Here we report that ASPP1/2 are required for proper mitotic progression. In ASPP1/2 co-depleted cells, the persistence of unaligned chromosomes and the reduction of tension across sister kinetochores on aligned chromosomes resulted in persistent spindle assembly checkpoint (SAC) activation. Using protein affinity purification methods, we searched for functional partners of ASPP1/2, and found that ASPP1/2 were associated with a subset of kinetochore proteins (Hec1, KNL-1, and CENP-F). It was found that ASPP1/2 act as PP1-targeting subunits to facilitate the interaction between PP1 and Hec1, and catalyze Hec1 (Ser165) dephosphorylation during late mitosis. These observations revealed a previously unrecognized function of ASPP1/2 in chromosome segregation and kinetochore-microtubule attachments that likely contributes to their roles in chromosome stability and tumor suppression.
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.|Institute of Biomedical Science, Fudan University, Shanghai, P. R. China.
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Youheng
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Heige
authors.initials: H
authors.lastname: Saiyin
authors.affiliation: Department of Gastroenterology, Jiangxi Institute of Gastroenterology & Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, P. R. China.
authors.forename: Dejie
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Jintao
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Reziya
authors.initials: R
authors.lastname: Wumaier
authors.affiliation: Institute of Biomedical Science, Fudan University, Shanghai, P. R. China.
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Pathology, The University of Arizona Medical Center, Tuscan, AZ, USA.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Long
authors.initials: L
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Chenji
authors.initials: C
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D020090:Chromosome Segregation; D003598:Cytoskeletal Proteins; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000201:enzymology*; D008840:Microfilament Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000201:enzymology*; D008938:Mitosis; D046912:Multiprotein Complexes; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002868:Chromosomal Proteins, Non-Histone; D003598:Cytoskeletal Proteins; C472643:Knl1 protein, human; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; C120529:NDC80 protein, human; D009687:Nuclear Proteins; C498406:PPP1R13B protein, human; C495901:TP53 protein, human; C090468:TP53BP2 protein, human; D016159:Tumor Suppressor Protein p53; C094772:centromere protein F; D054645:Protein Phosphatase 1
keywords: Chromosome Section; chromosome segregation; dephosphorylation; kinetochore-microtubule attachment; protein phosphatase 1; spindle assembly checkpoint