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Cyclin D-Cdk4,6 drives cell cycle progression via the retinoblastoma protein’s C-terminal helix

Benjamin R. Topacio, Evgeny Zatulovskiy, Sandra Cristea, Shicong Xie, Carrie S. Tambo, Seth M. Rubin, Julien Sage, Mardo Kõivomägi, Jan M. Skotheim
doi: https://doi.org/10.1101/397448
Benjamin R. Topacio
1Department of Biology, Stanford University, Stanford, CA 94305, USA
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Evgeny Zatulovskiy
1Department of Biology, Stanford University, Stanford, CA 94305, USA
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Sandra Cristea
2Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
3Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Shicong Xie
1Department of Biology, Stanford University, Stanford, CA 94305, USA
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Carrie S. Tambo
4Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA
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Seth M. Rubin
4Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA
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Julien Sage
2Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
3Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Mardo Kõivomägi
1Department of Biology, Stanford University, Stanford, CA 94305, USA
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  • For correspondence: mardok@stanford.edu skotheim@stanford.edu
Jan M. Skotheim
1Department of Biology, Stanford University, Stanford, CA 94305, USA
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  • For correspondence: mardok@stanford.edu skotheim@stanford.edu
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Summary

The cyclin-dependent kinases Cdk4 and Cdk6 form complexes with D-type cyclins to drive cell proliferation. A well-known target of cyclin D-Cdk4,6 is the retinoblastoma protein, Rb, which inhibits cell cycle progression until its inactivation by phosphorylation. However, the role of cyclin D-Cdk4,6 phosphorylation of Rb in cell cycle progression is unclear because Rb can be phosphorylated by other cyclin-Cdk complexes and cyclin D-Cdk4,6 complexes have other targets that may drive cell division. Here, we show that cyclin D-Cdk4,6 docks one side of an alpha-helix in the C-terminus of Rb, which is not recognized by cyclins E, A, and B. This helix-based docking mechanism is shared by the p107 and p130 Rb-family members across metazoans. Mutation of the Rb C-terminal helix prevents phosphorylation, promotes G1 arrest, and enhances Rb’s tumor suppressive function. Our work conclusively demonstrates that the cyclin D-Rb interaction drives cell division and defines a new class of cyclin-based docking mechanisms.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 21, 2018.
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Cyclin D-Cdk4,6 drives cell cycle progression via the retinoblastoma protein’s C-terminal helix
Benjamin R. Topacio, Evgeny Zatulovskiy, Sandra Cristea, Shicong Xie, Carrie S. Tambo, Seth M. Rubin, Julien Sage, Mardo Kõivomägi, Jan M. Skotheim
bioRxiv 397448; doi: https://doi.org/10.1101/397448
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Cyclin D-Cdk4,6 drives cell cycle progression via the retinoblastoma protein’s C-terminal helix
Benjamin R. Topacio, Evgeny Zatulovskiy, Sandra Cristea, Shicong Xie, Carrie S. Tambo, Seth M. Rubin, Julien Sage, Mardo Kõivomägi, Jan M. Skotheim
bioRxiv 397448; doi: https://doi.org/10.1101/397448

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