Cyclin K regulates prereplicative complex assembly to promote mammalian cell proliferation

Tingjun Lei, Peixuan Zhang, Xudong Zhang, Xue Xiao, Jingli Zhang, Tong Qiu, Qian Dai, Yujun Zhang, Ling Min, Qian Li, Rutie Yin, Ping Ding, Ni Li, Yi Qu, Dezhi Mu, Jun Qin, Xiaofeng Zhu (), Zhi-Xiong Xiao () and Qintong Li ()
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Tingjun Lei: Sichuan University
Peixuan Zhang: Sichuan University
Xudong Zhang: Sichuan University
Xue Xiao: Sichuan University
Jingli Zhang: Hospital 363 of Aviation Industry Corporation of China
Tong Qiu: Sichuan University
Qian Dai: Sichuan University
Yujun Zhang: Sichuan University
Ling Min: Sichuan University
Qian Li: Hospital 363 of Aviation Industry Corporation of China
Rutie Yin: Sichuan University
Ping Ding: Sichuan Cunde Therapeutics
Ni Li: University of Chinese Academy of Sciences
Yi Qu: Sichuan University
Dezhi Mu: Sichuan University
Jun Qin: University of Chinese Academy of Sciences
Xiaofeng Zhu: Sichuan University
Zhi-Xiong Xiao: Sichuan University
Qintong Li: Sichuan University

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-04258-w

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