7月17日，Cell Res雜志在線報道了DNA修復(fù)酶N-甲基化嘌呤DNA糖基化酶可與p53基因協(xié)同作用調(diào)節(jié)腫瘤細(xì)胞對烷化劑的敏感性。
烷化劑誘發(fā)的全基因組堿基的損害，主要是由N-甲基化嘌呤DNA糖基化酶（MPG）修復(fù),。在某些類型的腫瘤細(xì)胞中表達(dá)升高的MPG賦予細(xì)胞對烷基化劑更高的敏感度，因為MPG誘導(dǎo)的無嘌呤/ 無嘧啶（AP）的位點(diǎn)，引發(fā)更多的DNA鏈斷裂,。然而，藥物敏感或不敏感的決定因素仍不清楚,。
本研究發(fā)現(xiàn),，p53狀態(tài)與MPG協(xié)作,，在這個過程中發(fā)揮舉足輕重的作用。 MPG在乳腺癌,，肺癌和結(jié)腸癌（分別為38.7％,，43.4％和25.3％）中表達(dá)陽性，但在所有癌旁正常組織為陰性,。 在未受到烷化劑應(yīng)激壓力的細(xì)胞中,，MPG直接結(jié)合到腫瘤抑制基因p53和并抑制p53的活性。過表達(dá)MPG下調(diào),，而去除MPG表達(dá)上調(diào),，P53下游抑制細(xì)胞周期進(jìn)程的基因，包括P21,，14-3-3σ和GADD45表達(dá)水平,，但不會影響促凋亡基因的表達(dá)。
p53蛋白與DNA結(jié)合結(jié)構(gòu)域的相互作用需要MPG的N-端區(qū)域,。在DNA烷基化試劑的刺激下,，p53野生型腫瘤細(xì)胞中的P53脫離MPG，并誘導(dǎo)細(xì)胞生長停滯,。然后,，AP位點(diǎn)被有效地修復(fù)，從而導(dǎo)致對烷化劑不敏感,。相比之下,，在p53突變的細(xì)胞，修復(fù)AP位點(diǎn)的效率較低,。
本研究作為第一個直接證據(jù)表明,，DNA修復(fù)酶可作為P53一種選擇性的調(diào)節(jié)因子。這些發(fā)現(xiàn)提供了在癌癥治療中MPG和p53之間的功能聯(lián)系的新證據(jù),。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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PMID:
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.
