Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
Cancer Res. 2012 Jun 1;72(11):2802-13. doi: 10.1158/0008-5472.CAN-11-3152. Epub 2012 Apr 9.
In precancerous and cancerous lesions, excessive growth signals resulting from activation of oncogenes or loss of tumor suppressor genes lead to intensive replication stress, which is recognized by a high level of replication-associated DNA double-strand breaks (DSB). However, the molecular mechanism by which cells alleviate excessive replication stress remains unclear. In this study, we report that the human nuclease/helicase DNA2 facilitates homologous recombination to repair replication-associated DNA DSBs, thereby providing cells with survival advantages under conditions of replication stress. The nuclease activity of DNA2 was required for DSB end resection, which allowed subsequent recruitment of RPA and RAD51 to repair DSBs and restart replication. More importantly, DNA2 expression was significantly increased in human cancers and its expression correlated with patient outcome. Our findings therefore indicate that enhanced activity of DSB resection likely constitutes one mechanism whereby precancerous and cancerous cells might alleviate replication stress.
在癌前病变和癌症病变中，由于癌基因的激活或肿瘤抑制基因的缺失导致过度的生长信号，从而导致密集的复制应激，这被高水平的复制相关的 DNA 双链断裂（DSB）所识别。然而，细胞缓解过度复制应激的分子机制尚不清楚。在这项研究中，我们报告人类核酸酶/解旋酶 DNA2 促进同源重组以修复复制相关的 DNA DSB，从而在复制应激条件下为细胞提供生存优势。DNA2 的核酸酶活性对于 DSB 末端切除是必需的，这允许随后招募 RPA 和 RAD51 来修复 DSB 并重新启动复制。更重要的是，DNA2 的表达在人类癌症中显著增加，其表达与患者预后相关。因此，我们的研究结果表明，DSB 切除活性的增强可能是癌前病变和癌细胞缓解复制应激的一种机制。
