近日，一项由上海交通大学医学院附属仁济医院干细胞研究中心高建新教授领衔的研究新近肿瘤基因领域有了新突破，生殖干细胞基因PIWIL2被认为在肿瘤的早期发生中扮演重要角色。
有关人士表示，这有可能为将来肿瘤的早期防治提供新的手段与途径。
肿瘤作为目前人类健康的第一大杀手，已为全球各国的科学家和研究人员广泛关注。肿瘤的发生是始于细胞内DNA受到损伤后发生基因突变，致使细胞功能改变，细胞增殖无法控制而致。DNA受损每天都在人体内发生，而受损后，人体自身机制会对其进行修复，成为早期预防肿瘤发生的一道天然屏障。
研究发现，DNA修复过程与染色质解链，修复蛋白激活并积聚到损伤部位有关。当前，国际上关于DNA自身修复的研究多聚焦于染色质松弛、解链后的修复过程。对于在DNA修复早期的关键步骤，染色质是如何松弛、解链的机制，了解甚少。
有关人士告诉记者，正常情况下，PIWIL2仅表达在睾丸的生殖干细胞和精原细胞中。 2010年，研究团队发现PIWIL2基因的异位、异化激活而产生Piwil2-like(PL2L)蛋白与肿瘤干细胞的发展有关。最近，他们又发现PIWIL2基因在由电离辐射、紫外线照射以及化学药剂等诱致的DNA损伤的修复中扮演非常重要的角色。
高建新教授介绍说，在DNA未受损的情况下，细胞内的PIWIL2基因是基本沉默的。当受到急性辐射或化学药物作用等导致DNA受损时，原本沉默的PIWIL2基因会被短暂激活，参与调节染色质松弛、解链，促进DNA修复。细胞染色质紧密的双链结构得到松弛是实现其它蛋白质对染色质内部进行准确、有效修复的关键。在修复后，PIWIL2基因又恢复到原有水平。
对于缺陷细胞而言，当受损DNA由于缺少PIWIL2基因而无法成功解链时，便无法完成对DNA的修复，此时，细胞就可能走向衰老、凋亡或向肿瘤细胞转化，丧失自身对细胞分裂的控制的功能，导致肿瘤形成。
由于这一修复过程处于肿瘤发生的早期，研究者认为，阐明PIWIL2基因在DNA修复过程中所扮演的角色，将为深入研究PIWIL2基因的生物学功能以及癌症防治的潜在手段方面提供新视角。此外，研究者还指出，PIWIL2基因今后有可能作为一个新的生物标记，来检测、评估人体受到急性辐射所造成的伤害。
该研究成果于2011年11月16日发表于《PLoS ONE》杂志。参与合作研究人员来自美国俄亥俄州立大学综合癌症中心，郑州大学第一附属医院， 美国加州大学戴维斯分校放射肿瘤科等。(生物谷 Bioon.com)
doi:10.1371/journal.pone.0027154
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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.
