近日,，一項(xiàng)由上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院干細(xì)胞研究中心高建新教授領(lǐng)銜的研究新近腫瘤基因領(lǐng)域有了新突破，生殖干細(xì)胞基因PIWIL2被認(rèn)為在腫瘤的早期發(fā)生中扮演重要角色。
有關(guān)人士表示,，這有可能為將來(lái)腫瘤的早期防治提供新的手段與途徑,。
腫瘤作為目前人類(lèi)健康的第一大殺手，已為全球各國(guó)的科學(xué)家和研究人員廣泛關(guān)注,。腫瘤的發(fā)生是始于細(xì)胞內(nèi)DNA受到損傷后發(fā)生基因突變,，致使細(xì)胞功能改變，細(xì)胞增殖無(wú)法控制而致,。DNA受損每天都在人體內(nèi)發(fā)生,，而受損后，人體自身機(jī)制會(huì)對(duì)其進(jìn)行修復(fù),，成為早期預(yù)防腫瘤發(fā)生的一道天然屏障,。
研究發(fā)現(xiàn)，DNA修復(fù)過(guò)程與染色質(zhì)解鏈,，修復(fù)蛋白激活并積聚到損傷部位有關(guān),。當(dāng)前，國(guó)際上關(guān)于DNA自身修復(fù)的研究多聚焦于染色質(zhì)松弛,、解鏈后的修復(fù)過(guò)程,。對(duì)于在DNA修復(fù)早期的關(guān)鍵步驟，染色質(zhì)是如何松弛,、解鏈的機(jī)制，了解甚少,。
有關(guān)人士告訴記者,，正常情況下，PIWIL2僅表達(dá)在睪丸的生殖干細(xì)胞和精原細(xì)胞中,。 2010年,，研究團(tuán)隊(duì)發(fā)現(xiàn)PIWIL2基因的異位、異化激活而產(chǎn)生Piwil2-like(PL2L)蛋白與腫瘤干細(xì)胞的發(fā)展有關(guān),。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(xué)藥劑等誘致的DNA損傷的修復(fù)中扮演非常重要的角色,。
高建新教授介紹說(shuō),，在DNA未受損的情況下，細(xì)胞內(nèi)的PIWIL2基因是基本沉默的,。當(dāng)受到急性輻射或化學(xué)藥物作用等導(dǎo)致DNA受損時(shí),，原本沉默的PIWIL2基因會(huì)被短暫激活，參與調(diào)節(jié)染色質(zhì)松弛,、解鏈,，促進(jìn)DNA修復(fù)。細(xì)胞染色質(zhì)緊密的雙鏈結(jié)構(gòu)得到松弛是實(shí)現(xiàn)其它蛋白質(zhì)對(duì)染色質(zhì)內(nèi)部進(jìn)行準(zhǔn)確、有效修復(fù)的關(guān)鍵,。在修復(fù)后,，PIWIL2基因又恢復(fù)到原有水平。
對(duì)于缺陷細(xì)胞而言,，當(dāng)受損DNA由于缺少PIWIL2基因而無(wú)法成功解鏈時(shí),，便無(wú)法完成對(duì)DNA的修復(fù)，此時(shí),，細(xì)胞就可能走向衰老,、凋亡或向腫瘤細(xì)胞轉(zhuǎn)化，喪失自身對(duì)細(xì)胞分裂的控制的功能,，導(dǎo)致腫瘤形成,。
由于這一修復(fù)過(guò)程處于腫瘤發(fā)生的早期，研究者認(rèn)為,，闡明PIWIL2基因在DNA修復(fù)過(guò)程中所扮演的角色,，將為深入研究PIWIL2基因的生物學(xué)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(gè)新的生物標(biāo)記，來(lái)檢測(cè),、評(píng)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(lái)自美國(guó)俄亥俄州立大學(xué)綜合癌癥中心,，鄭州大學(xué)第一附屬醫(yī)院,， 美國(guó)加州大學(xué)戴維斯分校放射腫瘤科等。(生物谷 Bioon.com)
doi:10.1371/journal.pone.0027154
PMC:
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.
