7月17日,Cell Res杂志在线报道了DNA修复酶N-甲基化嘌呤DNA糖基化酶可与p53基因协同作用调节肿瘤细胞对烷化剂的敏感性。
烷化剂诱发的全基因组碱基的损害,主要是由N-甲基化嘌呤DNA糖基化酶(MPG)修复。在某些类型的肿瘤细胞中表达升高的MPG赋予细胞对烷基化剂更高的敏感度,因为MPG诱导的无嘌呤/ 无嘧啶(AP)的位点,引发更多的DNA链断裂。然而,药物敏感或不敏感的决定因素仍不清楚。
本研究发现,p53状态与MPG协作,在这个过程中发挥举足轻重的作用。 MPG在乳腺癌,肺癌和结肠癌(分别为38.7%,43.4%和25.3%)中表达阳性,但在所有癌旁正常组织为阴性。 在未受到烷化剂应激压力的细胞中,MPG直接结合到肿瘤抑制基因p53和并抑制p53的活性。过表达MPG下调,而去除MPG表达上调,P53下游抑制细胞周期进程的基因,包括P21,14-3-3σ和GADD45表达水平,但不会影响促凋亡基因的表达。
p53蛋白与DNA结合结构域的相互作用需要MPG的N-端区域。在DNA烷基化试剂的刺激下,p53野生型肿瘤细胞中的P53脱离MPG,并诱导细胞生长停滞。然后,AP位点被有效地修复,从而导致对烷化剂不敏感。相比之下,在p53突变的细胞,修复AP位点的效率较低。
本研究作为第一个直接证据表明,DNA修复酶可作为P53一种选择性的调节因子。这些发现提供了在癌症治疗中MPG和p53之间的功能联系的新证据。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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N-methylpurine DNA glycosylase inhibits p53-mediated cell cycle arrest and coordinates with p53 to determine sensitivity to alkylating agents
Shanshan Song1,2,3, Guichun Xing2,3, Lin Yuan2,3, Jian Wang2,3, Shan Wang2,3, Yuxin Yin4, Chunyan Tian2,3, Fuchu He1,2,3 and Lingqiang Zhang2
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.