Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
Cell Res. 2012 Aug;22(8):1285-303. doi: 10.1038/cr.2012.107. Epub 2012 Jul 17.
Alkylating agents induce genome-wide base damage, which is repaired mainly by N-methylpurine DNA glycosylase (MPG). An elevated expression of MPG in certain types of tumor cells confers higher sensitivity to alkylation agents because MPG-induced apurinic/apyrimidic (AP) sites trigger more strand breaks. However, the determinant of drug sensitivity or insensitivity still remains unclear. Here, we report that the p53 status coordinates with MPG to play a pivotal role in such process. MPG expression is positive in breast, lung and colon cancers (38.7%, 43.4% and 25.3%, respectively) but negative in all adjacent normal tissues. MPG directly binds to the tumor suppressor p53 and represses p53 activity in unstressed cells. The overexpression of MPG reduced, whereas depletion of MPG increased, the expression levels of pro-arrest gene downstream of p53 including p21, 14-3-3σ and Gadd45 but not proapoptotic ones. The N-terminal region of MPG was specifically required for the interaction with the DNA binding domain of p53. Upon DNA alkylation stress, in p53 wild-type tumor cells, p53 dissociated from MPG and induced cell growth arrest. Then, AP sites were repaired efficiently, which led to insensitivity to alkylating agents. By contrast, in p53-mutated cells, the AP sites were repaired with low efficacy. To our knowledge, this is the first direct evidence to show that a DNA repair enzyme functions as a selective regulator of p53, and these findings provide new insights into the functional linkage between MPG and p53 in cancer therapy.
烷化剂会诱导全基因组碱基损伤，这种损伤主要由 N-甲基嘌呤 DNA 糖基化酶（MPG）修复。在某些类型的肿瘤细胞中，MPG 的高表达赋予了它们对烷化剂更高的敏感性，因为 MPG 诱导的无嘌呤/无嘧啶（AP）位点会引发更多的链断裂。然而，药物敏感性或不敏感性的决定因素仍不清楚。在这里，我们报告称，p53 状态与 MPG 一起在这个过程中发挥关键作用。MPG 在乳腺癌、肺癌和结肠癌中呈阳性（分别为 38.7%、43.4%和 25.3%），但在所有相邻的正常组织中均呈阴性。MPG 直接与肿瘤抑制因子 p53 结合，并在未受应激的细胞中抑制 p53 活性。MPG 的过表达降低了 p53 下游包括 p21、14-3-3σ 和 Gadd45 等促停滞基因的表达水平，但不影响促凋亡基因。MPG 的 N 端区域特异性地与 p53 的 DNA 结合域相互作用。在 DNA 烷化应激下，在 p53 野生型肿瘤细胞中，p53 从 MPG 上解离并诱导细胞生长停滞。然后，AP 位点被有效修复，从而导致对烷化剂不敏感。相比之下，在 p53 突变细胞中，AP 位点的修复效率较低。据我们所知，这是第一个直接证据表明一种 DNA 修复酶可作为 p53 的选择性调节剂，这些发现为 MPG 和 p53 在癌症治疗中的功能联系提供了新的见解。
