He Jinxue, Kang Xi, Yin Yuxin, Chao K S Clifford, Shen Wen H
Department of Radiation Oncology, Weill Medical College of Cornell University, New York 10065, USA.
Nat Commun. 2015 Jul 9;6:7620. doi: 10.1038/ncomms8620.
Faithful DNA replication is a cornerstone of genomic integrity. PTEN plays multiple roles in genome protection and tumour suppression. Here we report on the importance of PTEN in DNA replication. PTEN depletion leads to impairment of replication progression and stalled fork recovery, indicating an elevation of endogenous replication stress. Exogenous replication inhibition aggravates replication-originated DNA lesions without inducing S phase arrest in cells lacking PTEN, representing replication stress tolerance. iPOND analysis reveals the physical association of PTEN with DNA replication forks and PTEN-dependent recruitment of Rad51. PTEN deletion results in Rad51 dissociation from replication forks. Stalled replication forks in Pten-null cells can be reactivated by ectopic Rad51 or PTEN, the latter facilitating chromatin loading of Rad51. These data highlight the interplay of PTEN with Rad51 in promoting stalled fork restart. We propose that loss of PTEN may initiate a replication stress cascade that progressively deteriorates through the cell cycle.
精确的DNA复制是基因组完整性的基石。PTEN在基因组保护和肿瘤抑制中发挥多种作用。在此，我们报告PTEN在DNA复制中的重要性。PTEN缺失导致复制进程受损和停滞叉的恢复受阻，表明内源性复制应激增加。外源性复制抑制会加重缺乏PTEN的细胞中复制起源的DNA损伤，而不会诱导S期阻滞，这代表了复制应激耐受性。iPOND分析揭示了PTEN与DNA复制叉的物理关联以及PTEN依赖性的Rad51募集。PTEN缺失导致Rad51从复制叉解离。Pten基因敲除细胞中停滞的复制叉可通过异位表达Rad51或PTEN重新激活，后者促进Rad51的染色质加载。这些数据突出了PTEN与Rad51在促进停滞叉重新启动中的相互作用。我们提出，PTEN的缺失可能引发一个复制应激级联反应，该反应在细胞周期中会逐渐恶化。
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