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Cell Rep. 2015 Nov 17;13(7):1295-1303. doi: 10.1016/j.celrep.2015.10.016. Epub 2015 Nov 5.

PTEN Controls the DNA Replication Process through MCM2 in Response to Replicative Stress.

Author information

1
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.
2
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.

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.

PMID:
26549452
DOI:
10.1016/j.celrep.2015.10.016
[Indexed for MEDLINE]
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