Ubiquitin Ligase RNF20/40 Facilitates Spindle Assembly and Promotes Breast Carcinogenesis Through Stabilizing Motor Protein Eg5

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Aug 26

PMID 27557628

Citations 34

Authors

Yang Duan

Dawei Huo

Jie Gao

Heng Wu

Zheng Ye

Zhe Liu

Kai Zhang

Lin Shan

Xing Zhou

Yue Wang

Dongxue Su

Xiang Ding

Lei Shi

Yan Wang

Yongfeng Shang

Chenghao Xuan

Affiliations

Soon will be listed here.

Abstract

Whether transcriptional regulators are functionally involved in mitosis is a fundamental question in cell biology. Here we report that the RNF20/40 complex, a major ubiquitin ligase catalysing histone H2B monoubiquitination, interacts with the motor protein Eg5 during mitosis and participates in spindle assembly. We show that the RNF20/40 complex monoubiquitinates and stabilizes Eg5. Loss of RNF20/40 results in spindle assembly defects, cell cycle arrest and apoptosis. Consistently, depletion of either RNF20/40 or Eg5 suppresses breast cancer in vivo. Significantly, RNF20/40 and Eg5 are concurrently upregulated in human breast carcinomas and high Eg5 expression is associated with poorer overall survival of patients with luminal A, or B, breast cancer. Our study uncovers an important spindle assembly role of the RNF20/40 complex, and implicates the RNF20/40-Eg5 axis in breast carcinogenesis, supporting the pursuit of these proteins as potential targets for breast cancer therapeutic interventions.

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References

Ding S, Nishizawa K, Kobayashi T, Oishi S, Lv J, Fujii N . A potent chemotherapeutic strategy for bladder cancer: (S)-methoxy-trityl-L-cystein, a novel Eg5 inhibitor. J Urol. 2010; 184(3):1175-81. DOI: 10.1016/j.juro.2010.04.073. View

Ferenz N, Gable A, Wadsworth P . Mitotic functions of kinesin-5. Semin Cell Dev Biol. 2010; 21(3):255-9. PMC: 2844466. DOI: 10.1016/j.semcdb.2010.01.019. View

Smith E, Hegarat N, Vesely C, Roseboom I, Larch C, Streicher H . Differential control of Eg5-dependent centrosome separation by Plk1 and Cdk1. EMBO J. 2011; 30(11):2233-45. PMC: 3117641. DOI: 10.1038/emboj.2011.120. View

Bakr El-Nassan H . Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents. Eur J Med Chem. 2013; 62:614-31. DOI: 10.1016/j.ejmech.2013.01.031. View

Robzyk K, Recht J, Osley M . Rad6-dependent ubiquitination of histone H2B in yeast. Science. 2000; 287(5452):501-4. DOI: 10.1126/science.287.5452.501. View

Sun Z, Allis C . Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature. 2002; 418(6893):104-8. DOI: 10.1038/nature00883. View

Zhang F, Yu X . WAC, a functional partner of RNF20/40, regulates histone H2B ubiquitination and gene transcription. Mol Cell. 2011; 41(4):384-97. PMC: 3062166. DOI: 10.1016/j.molcel.2011.01.024. View

Xin L, Zhou G, Song W, Wu X, Wei G, Hao D . Exploring cellular memory molecules marking competent and active transcriptions. BMC Mol Biol. 2007; 8:31. PMC: 1884170. DOI: 10.1186/1471-2199-8-31. View

Sakowicz R, Finer J, Beraud C, Crompton A, Lewis E, Fritsch A . Antitumor activity of a kinesin inhibitor. Cancer Res. 2004; 64(9):3276-80. DOI: 10.1158/0008-5472.can-03-3839. View

10.

Thomas J, Zhang Y, Wei Y, Cho J, Morris L, Wang H . Rab1A is an mTORC1 activator and a colorectal oncogene. Cancer Cell. 2014; 26(5):754-69. PMC: 4288827. DOI: 10.1016/j.ccell.2014.09.008. View

11.

Castillo A, Morse 3rd H, Godfrey V, Naeem R, Justice M . Overexpression of Eg5 causes genomic instability and tumor formation in mice. Cancer Res. 2007; 67(21):10138-47. DOI: 10.1158/0008-5472.CAN-07-0326. View

12.

Pavri R, Zhu B, Li G, Trojer P, Mandal S, Shilatifard A . Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II. Cell. 2006; 125(4):703-17. DOI: 10.1016/j.cell.2006.04.029. View

13.

Jentsch S, McGrath J, Varshavsky A . The yeast DNA repair gene RAD6 encodes a ubiquitin-conjugating enzyme. Nature. 1987; 329(6135):131-4. DOI: 10.1038/329131a0. View

14.

Liu M, Wang X, Yang Y, Li D, Ren H, Zhu Q . Ectopic expression of the microtubule-dependent motor protein Eg5 promotes pancreatic tumourigenesis. J Pathol. 2010; 221(2):221-8. DOI: 10.1002/path.2706. View

15.

Duhl D, Renhowe P . Inhibitors of kinesin motor proteins--research and clinical progress. Curr Opin Drug Discov Devel. 2005; 8(4):431-6. View

16.

Dover J, Schneider J, Tawiah-Boateng M, Wood A, Dean K, Johnston M . Methylation of histone H3 by COMPASS requires ubiquitination of histone H2B by Rad6. J Biol Chem. 2002; 277(32):28368-71. DOI: 10.1074/jbc.C200348200. View

17.

Mayer T, Kapoor T, Haggarty S, King R, Schreiber S, Mitchison T . Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science. 1999; 286(5441):971-4. DOI: 10.1126/science.286.5441.971. View

18.

Hicke L . Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol. 2001; 2(3):195-201. DOI: 10.1038/35056583. View

19.

Kapitein L, Peterman E, Kwok B, Kim J, Kapoor T, Schmidt C . The bipolar mitotic kinesin Eg5 moves on both microtubules that it crosslinks. Nature. 2005; 435(7038):114-8. DOI: 10.1038/nature03503. View

20.

Ding S, Xing N, Lu J, Zhang H, Nishizawa K, Liu S . Overexpression of Eg5 predicts unfavorable prognosis in non-muscle invasive bladder urothelial carcinoma. Int J Urol. 2011; 18(6):432-8. DOI: 10.1111/j.1442-2042.2011.02751.x. View