mTOR Signaling Upregulates CDC6 via Suppressing miR-3178 and Promotes the Loading of DNA Replication Helicase

Xianjin Wu, Shenghua Li, Xing Hu, Xiaoliang Xiang, Megan Halloran, Linlin Yang, Terence M. Williams, Peter J Houghton, Changxian Shen, Zhengfu He

Research output: Contribution to journalArticle

Abstract

mTOR signaling pathway is deregulated in most cancers and uncontrolled cell cycle progression is a hallmark of cancer cell. However, the precise molecular mechanisms of the regulation of DNA replication and chromatin metabolism by mTOR signaling are largely unknown. We herein report that mTOR signaling promotes the loading of MCM2-7 helicase onto chromatin and upregulates DNA replication licensing factor CDC6. Pharmacological inhibition of mTOR kinase resulted in CHK1 checkpoint activation and decreased MCM2-7 replication helicase and PCNA associated with chromatins. Further pharmacological and genetic studies demonstrated CDC6 is positively controlled by mTORC1-S6K1 and mTORC2 signaling. miRNA screening revealed mTOR signaling suppresses miR-3178 thereby upregulating CDC6. Analysis of TCGA data found that CDC6 is overexpressed in most cancers and associates with the poor survival of cancer patients. Our findings suggest that mTOR signaling may control DNA replication origin licensing and replisome stability thereby cell cycle progression through CDC6 regulation.

Original languageEnglish (US)
Article number9805
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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DNA Helicases
DNA Replication
Up-Regulation
Minichromosome Maintenance Proteins
Chromatin
Licensure
Neoplasms
Cell Cycle
Pharmacology
Replication Origin
Proliferating Cell Nuclear Antigen
MicroRNAs
Phosphotransferases
Survival

ASJC Scopus subject areas

  • General

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mTOR Signaling Upregulates CDC6 via Suppressing miR-3178 and Promotes the Loading of DNA Replication Helicase. / Wu, Xianjin; Li, Shenghua; Hu, Xing; Xiang, Xiaoliang; Halloran, Megan; Yang, Linlin; Williams, Terence M.; Houghton, Peter J; Shen, Changxian; He, Zhengfu.

In: Scientific reports, Vol. 9, No. 1, 9805, 01.12.2019.

Research output: Contribution to journalArticle

Wu, Xianjin ; Li, Shenghua ; Hu, Xing ; Xiang, Xiaoliang ; Halloran, Megan ; Yang, Linlin ; Williams, Terence M. ; Houghton, Peter J ; Shen, Changxian ; He, Zhengfu. / mTOR Signaling Upregulates CDC6 via Suppressing miR-3178 and Promotes the Loading of DNA Replication Helicase. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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AU - Halloran, Megan

AU - Yang, Linlin

AU - Williams, Terence M.

AU - Houghton, Peter J

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