Priority Research Papers:
CDK1 promotes nascent DNA synthesis and induces resistance of cancer cells to DNA-damaging therapeutic agents
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Hongwei Liao1,2, Fang Ji1,2, Xinwei Geng1,2, Meichun Xing1,2, Wen Li1, Zhihua Chen1, Huahao Shen1 and Songmin Ying1,2
1 Department of Respiratory and Critical Care Medicine of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
2 Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
Songmin Ying, email:
Keywords: CDK1, DNA replication, chemotherapy resistance, DNA damage response, PARP
Received: August 02, 2017 Accepted: September 20, 2017 Published: October 10, 2017
Cyclin dependent kinase 1 (CDK1) is essential for cell viability and plays a vital role in many biological events including cell cycle control, DNA damage repair, and checkpoint activation. Here, we identify an unanticipated role for CDK1 in promoting nascent DNA synthesis during S-phase. We report that a short duration of CDK1 inhibition, which does not perturb cell cycle progression, triggers a replication-associated DNA damage response (DDR). This DDR is associated with a disruption of replication fork progression and leads to genome instability. Moreover, we show that compromised CDK1 activity dramatically increases the efficacy of chemotherapeutic agents that kill cancer cells through perturbing DNA replication, including Olaparib, an FDA approved PARP inhibitor. Our study has revealed an important role for CDK1 in the DNA replication program, and suggests that the therapeutic targeting CDK1 may be a novel approach for combination chemotherapy.
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