title: Stabilization of MCRS1 by BAP1 prevents chromosome instability in renal cell carcinoma.
abstract: Characterization of the exome and genome of carcinoma (ccRCC) by next-generation sequencing identified numerous genetic alternations. BRCA1-associated protein-1 (BAP1) was identified as one of the most frequently mutated genes in ccRCC, suggesting that BAP1 is a potential key driver for ccRCC cancer initiation and progression. However, how BAP1 mutations contribute to ccRCC remains to be elucidated. BAP1 is a nuclear de-ubiquitinating enzyme and cleaves the ubiquitin chain from the substrates. Here, we identified MCRS1 as a bona fide substrate for BAP1. MCRS1 is a component of the centrosome proteins, and plays an essential role in spindle assembly. BAP1 binds to MCRS1 and stabilizes MCRS1 by de-ubiquitination. BAP1 contributes to chromosome stability partially via MCRS1. A positive correlation was identified between BAP1 and MCRS1 expression in ccRCC tissues. Both BAP1 loss and MCRS1 down-regulation in ccRCC were associated with adverse clinicopathological features. This study revealed a novel mechanism for BAP1 involved in MCRS1 stability regulation, and provided insight in understanding the relationship between BAP1 mutations and chromosome instability in ccRCC.
authors: Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 100 Haining Road, Shanghai 200080, China.
authors: Jingtao
authors: J
authors: Peng
authors: Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 100 Haining Road, Shanghai 200080, China.
authors: Jian
authors: J
authors: Ma
authors: Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 100 Haining Road, Shanghai 200080, China.
authors: Weiguo
authors: W
authors: Li
authors: Department of Urology, Inner Mongolia Autonomous Region Peoples Hospital, 20 Zhaowuda Road, Hohhot 010017, China.
authors: Ren
authors: R
authors: Mo
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, China.
authors: Pingzhao
authors: P
authors: Zhang
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, China.
authors: Kun
authors: K
authors: Gao
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, China.
authors: Xiaofeng
authors: X
authors: Jin
authors: Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 100 Haining Road, Shanghai 200080, China.
authors: Jiantao
authors: J
authors: Xiao
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, China. Electronic address: chenjiwang@fudan.edu.cn.
authors: Chenji
authors: C
authors: Wang
authors: Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 100 Haining Road, Shanghai 200080, China. Electronic address: jief67@sina.com.
authors: Jie
authors: J
authors: Fan
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D043171:Chromosomal Instability; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D016601:RNA-Binding Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D043222:Ubiquitin Thiolesterase / Q000502:physiology*; D054875:Ubiquitination
chemical_list: C400134:BAP1 protein, human; C113292:MCRS1 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: BAP1; Chromosome instability; Clear cell renal cell carcinoma; De-ubiquitination; MCRS1