近日,，一項由上海交通大學醫(yī)學院附屬仁濟醫(yī)院干細胞研究中心高建新教授領銜的研究新近腫瘤基因領域有了新突破，生殖干細胞基因PIWIL2被認為在腫瘤的早期發(fā)生中扮演重要角色。
有關人士表示,，這有可能為將來腫瘤的早期防治提供新的手段與途徑,。
腫瘤作為目前人類健康的第一大殺手，已為全球各國的科學家和研究人員廣泛關注,。腫瘤的發(fā)生是始于細胞內DNA受到損傷后發(fā)生基因突變,，致使細胞功能改變，細胞增殖無法控制而致,。DNA受損每天都在人體內發(fā)生,，而受損后，人體自身機制會對其進行修復,，成為早期預防腫瘤發(fā)生的一道天然屏障,。
研究發(fā)現(xiàn)，DNA修復過程與染色質解鏈,，修復蛋白激活并積聚到損傷部位有關,。當前，國際上關于DNA自身修復的研究多聚焦于染色質松弛,、解鏈后的修復過程,。對于在DNA修復早期的關鍵步驟，染色質是如何松弛,、解鏈的機制,，了解甚少,。
有關人士告訴記者,，正常情況下，PIWIL2僅表達在睪丸的生殖干細胞和精原細胞中,。 2010年,，研究團隊發(fā)現(xiàn)PIWIL2基因的異位、異化激活而產生Piwil2-like(PL2L)蛋白與腫瘤干細胞的發(fā)展有關,。最近,，他們又發(fā)現(xiàn)PIWIL2基因在由電離輻射、紫外線照射以及化學藥劑等誘致的DNA損傷的修復中扮演非常重要的角色,。
高建新教授介紹說,，在DNA未受損的情況下，細胞內的PIWIL2基因是基本沉默的。當受到急性輻射或化學藥物作用等導致DNA受損時,，原本沉默的PIWIL2基因會被短暫激活,，參與調節(jié)染色質松弛、解鏈,，促進DNA修復,。細胞染色質緊密的雙鏈結構得到松弛是實現(xiàn)其它蛋白質對染色質內部進行準確、有效修復的關鍵,。在修復后,，PIWIL2基因又恢復到原有水平。
對于缺陷細胞而言,，當受損DNA由于缺少PIWIL2基因而無法成功解鏈時,，便無法完成對DNA的修復，此時,，細胞就可能走向衰老,、凋亡或向腫瘤細胞轉化，喪失自身對細胞分裂的控制的功能,，導致腫瘤形成,。
由于這一修復過程處于腫瘤發(fā)生的早期，研究者認為,，闡明PIWIL2基因在DNA修復過程中所扮演的角色,，將為深入研究PIWIL2基因的生物學功能以及癌癥防治的潛在手段方面提供新視角。此外,，研究者還指出，PIWIL2基因今后有可能作為一個新的生物標記,，來檢測,、評估人體受到急性輻射所造成的傷害。
該研究成果于2011年11月16日發(fā)表于《PLoS ONE》雜志,。參與合作研究人員來自美國俄亥俄州立大學綜合癌癥中心,，鄭州大學第一附屬醫(yī)院， 美國加州大學戴維斯分校放射腫瘤科等,。(生物谷 Bioon.com)
doi:10.1371/journal.pone.0027154
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PMID:
Germline Stem Cell Gene PIWIL2 Mediates DNA Repair through Relaxation of Chromatin
De-Tao Yin, Qien Wang, Li Chen, Meng-Yao Liu, Chunhua Han, Qingtao Yan, Rulong Shen, Gang He, Wenrui Duan, Jian-Jian Li, Altaf Wani,, Jian-Xin Gao
DNA damage response (DDR) is an intrinsic barrier of cell to tumorigenesis initiated by genotoxic agents. However, the mechanisms underlying the DDR are not completely understood despite of extensive investigation. Recently, we have reported that ectopic expression of germline stem cell gene PIWIL2 is associated with tumor stem cell development, although the underlying mechanisms are largely unknown. Here we show that PIWIL2 is required for the repair of DNA-damage induced by various types of genotoxic agents. Upon ultraviolet (UV) irradiation, silenced PIWIL2 gene in normal human fibroblasts was transiently activated after treatment with UV light. This activation was associated with DNA repair, because Piwil2-deficienct mouse embryonic fibroblasts (mili-/- MEFs) were defective in cyclobutane pyrimidine dimers (CPD) repair after UV treatment. As a result, the UV-treated mili-/- MEFs were more susceptible to apoptosis, as characterized by increased levels of DNA damage-associated apoptotic proteins, such as active caspase-3, cleaved Poly (ADP-ribose) polymerase (PARP) and Bik. The impaired DNA repair in the mili-/- MEFs was associated with the reductions of histone H3 acetylation and chromatin relaxation, although the DDR pathway downstream chromatin relaxation appeared not to be directly affected by Piwil2. Moreover, guanine–guanine (Pt-[GG]) and double strand break (DSB) repair were also defective in the mili-/- MEFs treated by genotoxic chemicals Cisplatin and ionizing radiation (IR), respectively. The results indicate that Piwil2 can mediate DNA repair through an axis of Piwil2 → histone acetylation → chromatin relaxation upstream DDR pathways. The findings reveal a new role for Piwil2 in DNA repair and suggest that Piwil2 may act as a gatekeeper against DNA damage-mediated tumorigenesis.
