PTEN Controls the DNA Replication Process through MCM2 in Response to Replicative Stress
PTEN Controls the DNA Replication Process through MCM2 in Response to Replicative Stress
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PTEN 通过 MCM2 控制 DNA 复制过程以应对复制压力
DOI：
10.1016/j.celrep.2015.10.016
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发表时间：
2015-11-17
期刊：
影响因子：
8.8
通讯作者：
Yin, Yuxin
中科院分区：
文献类型：
--
作者：
Feng, Jiawen;Liang, Jing;Yin, Yuxin
PTEN是一种在人类癌症中经常突变的肿瘤抑制因子。PTEN抑制磷脂酰肌醇3-激酶（PI 3 K）-AKT级联，并且核PTEN通过多种机制保护基因组。在这里，我们报告说，PTEN与微小染色体维持复合物组分2（MCM 2），这是DNA复制所必需的物理关联。具体地，PTEN在丝氨酸41（S41）处使MCM 2去磷酸化，并限制复制应激下的复制叉进展。在复制停滞时，PTEN破坏导致不受限制的叉进展，这与表达磷酸模拟MCM 2突变体S41 D的细胞的表型相似。此外，PTEN对于防止复制应激下的染色体畸变是必需的。这项研究表明，PTEN通过MCM 2调节DNA复制，并且PTEN功能的丧失导致复制缺陷和基因组不稳定性。我们认为，PTEN通过复制特异性机制在维持遗传稳定性方面起着关键作用，这是PTEN肿瘤抑制活性的一个重要方面。
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.