title: PTEN Controls the DNA Replication Process through MCM2 in Response to Replicative Stress.
abstract: PTEN is a tumor suppressor frequently mutated in human cancers. PTEN inhibits the phosphatidylinositol 3-kinase (PI3K)-AKT cascade, and nuclear PTEN guards the genome by multiple mechanisms. Here, we report that PTEN physically associates with the minichromosome maintenance complex component 2 (MCM2), which is essential for DNA replication. Specifically, PTEN dephosphorylates MCM2 at serine 41 (S41) and restricts replication fork progression under replicative stress. PTEN disruption results in unrestrained fork progression upon replication stalling, which is similar to the phenotype of cells expressing the phosphomimic MCM2 mutant S41D. Moreover, PTEN is necessary for prevention of chromosomal aberrations under replication stress. This study demonstrates that PTEN regulates DNA replication through MCM2 and loss of PTEN function leads to replication defects and genomic instability. We propose that PTEN plays a critical role in maintaining genetic stability through a replication-specific mechanism, and this is a crucial facet of PTEN tumor suppressor activity.
authors.affiliation: Institute of Systems Biomedicine, Center for Molecular and Translational Medicine, Department of Pathology, School of Basic Medicine, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, PRC.
authors.forename: Jiawen
authors.initials: J
authors.lastname: Feng
authors.affiliation: Institute of Systems Biomedicine, Center for Molecular and Translational Medicine, Department of Pathology, School of Basic Medicine, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, PRC.
authors.forename: Jing
authors.initials: J
authors.lastname: Liang
authors.affiliation: Institute of Systems Biomedicine, Center for Molecular and Translational Medicine, Department of Pathology, School of Basic Medicine, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, PRC.
authors.forename: Jiaju
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Systems Biomedicine, Center for Molecular and Translational Medicine, Department of Pathology, School of Basic Medicine, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, PRC.
authors.forename: Yunqiao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Systems Biomedicine, Center for Molecular and Translational Medicine, Department of Pathology, School of Basic Medicine, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, PRC.
authors.forename: Hui
authors.initials: H
authors.lastname: Liang
authors.affiliation: Institute of Systems Biomedicine, Center for Molecular and Translational Medicine, Department of Pathology, School of Basic Medicine, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, PRC.
authors.forename: Xuyang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Systems Biomedicine, Center for Molecular and Translational Medicine, Department of Pathology, School of Basic Medicine, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, PRC.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McNutt
authors.affiliation: Institute of Systems Biomedicine, Center for Molecular and Translational Medicine, Department of Pathology, School of Basic Medicine, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, PRC. Electronic address: yinyuxin@hsc.pku.edu.cn.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Yin
mesh_terms: D043171:Chromosomal Instability; D004261:DNA Replication; D045325:HCT116 Cells; D006801:Humans; D064111:Minichromosome Maintenance Complex Component 2 / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013312:Stress, Physiological
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2