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Cyclin K regulates prereplicative complex assembly to promote mammalian cell proliferation
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Cyclin K regulates prereplicative complex assembly to promote mammalian cell proliferation
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Journal Article
Cyclin K regulates prereplicative complex assembly to promote mammalian cell proliferation
2018
Overview
The assembly of prereplicative complex (pre-RC) during G1 phase must be tightly controlled to sustain cell proliferation and maintain genomic stability. Mechanisms to prevent pre-RC formation in G2/M and S phases are well appreciated, whereas how cells ensure efficient pre-RC assembly during G1 is less clear. Here we report that cyclin K regulates pre-RC formation. We find that cyclin K expression positively correlates with cell proliferation, and knockdown of cyclin K or its cognate kinase CDK12 prevents the assembly of pre-RC in G1 phase. Mechanistically we uncover that cyclin K promotes pre-RC assembly by restricting cyclin E1 activity in G1. We identify a cyclin K-dependent, novel phosphorylation site in cyclin E1 that disrupts its interaction with CDK2. Importantly, this antagonistic relationship is largely recapitulated in cyclin E1-overexpressing tumors. We discuss the implications of our findings in light of recent reports linking cyclin K and CDK12 to human tumorigenesis.
Prereplicative complex (pre-RC) formation during G1 is fundamental for cell replication. Here the authors report a role for cyclin K in regulating pre-RC formation in mammalian cells by affecting cyclin E1 activity.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 42
/ 631/67
/ 96
/ Animals
/ Assembly
/ Breast Neoplasms - metabolism
/ Breast Neoplasms - pathology
/ Cyclin-Dependent Kinase 2 - genetics
/ Cyclin-Dependent Kinase 2 - metabolism
/ Cyclin-Dependent Kinases - genetics
/ Cyclin-Dependent Kinases - metabolism
/ Cyclins - antagonists & inhibitors
/ Female
/ G1 phase
/ G1 Phase Cell Cycle Checkpoints - genetics
/ G2 Phase Cell Cycle Checkpoints - genetics
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mice
/ Oncogene Proteins - genetics
/ Oncogene Proteins - metabolism
/ RNA, Small Interfering - genetics
/ RNA, Small Interfering - metabolism
/ S Phase Cell Cycle Checkpoints - genetics
/ Science
