ASPP1/2-PP1 complexes are required for chromosome segregation and kinetochore-microtubule attachments

// Pingzhao Zhang 1,2,* , Yuanyuan Zhang 1,* , Kun Gao 1 , Yuqi Wang 1 , Xiaofeng Jin 1 , Youheng Wei 1 , Heige Saiyin 1 , Dejie Wang 3 , Jintao Peng 4 , Jian Ma 4 , Yan Tang 1 , Reziya Wumaier 1 , Hongxiu Yu 2 , Yimin Dong 5 , Haojie Huang 6 , Long Yu 1 and Chenji Wang 1 1 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China 2 Institutes of Biomedical Sciences, Fudan University, Shanghai, P. R. China 3 Department of Gastroenterology, Jiangxi Institute of Gastroenterology & Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, P. R. China 4 Department of Urology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China 5 Department of Pathology, The University of Arizona Medical Center, Arizona, USA 6 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA * These authors have contributed equally to this work Correspondence to: Yu Long, email: // Chenji Wang, email: // Keywords : chromosome segregation, kinetochore-microtubule attachment, spindle assembly checkpoint, dephosphorylation, protein phosphatase 1, Chromosome Section Received : October 01, 2015 Accepted : November 02, 2015 Published : November 22, 2015 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.