2篇Nature:癌症基因组分析揭示启动子突变显著增加原因
2016/04/18
4月14日Nature上的两篇论文对而哪些变量影响癌症基因组中启动子点突变的频率进行审视,发现了存在将转录启动和DNA修复联系起来的机制的证据。


体细胞突变是癌症基因组进化的驱动力。由于染色质组织中的变异、DNA的可接近性和复制时间差,基因组体细胞的突变率似乎大有差异。然而哪些变量影响局部的突变率还是未知的。最近的癌症全基因组分析,在基因启动子内识别出了无数的体细胞点突变热点。只是正向选择可能无法充分地解释在癌症基因组中启动子点突变的频率。4月14日Nature上的两篇论文对这一关系进行审视,发现了存在将转录启动和DNA修复联系起来的机制的证据。

过千癌症基因组分析揭示启动子点突变和核苷酸切除修复有关

Jason Wong及同事分析了14个癌症类型的1161个人类癌症基因组,发现基因启动子上突变密度的增加与转录启动活动和核苷酸切除修复的损伤有关。启动子突变的密度可以与癌症对切除修复的依赖性关联起来。研究发现在基因启动子的DNase I酶的高度敏感位点(DHSs)中心点突变区域密度增加,突变了的DHSs和转录起始活性强烈相关。

研究人员观察在黑色素瘤中紫外线导致DNA损伤突变的信号显示启动子突变最大的富集,而在不是那么依赖核酸切除活性的癌症中比如结肠癌中,没有迹象显示这种富集。

研究结果表明转录和核酸切除修复存在相互作用,特别是在活性基因启动子导致本地化突变的高密度。从进化的角度来看它是有趣的转录起始耦合机制,允许基因启动子突变积累的加速。然而正如很多已分析的癌症基因组在启动子DHSs包含几十、数百的突变,在不少基因具有多个启动子的状况下,点突变效果对启动子活性可能是很强的。这个研究强调了需要仔细审查在癌症发展中基因启动子突变的需要。

皮肤癌样本揭示突变率的增加与切除修复的机会的降低有关

在第二个研究中,在癌症基因组Atlas计划中的36个皮肤癌样本里发现了类似的模式。Núria López-Bigas及同事报告了对来自黑素瘤的基因组数据所做的一项分析,发现在启动子区域内活跃转录因子结合点上的体细胞突变率增加。

使用最近提供的切除修复基因测序(XR-seq)数据,研究显示这些基因组区域内突变率的增加,可以用与蛋白相结合的DNA接触核苷酸切除修复的机会的降低来解释。这一发现对于理解在鉴定癌症驱动突变中的突变和DNA修复过程有重要意义。

研究结果表明,大多数在转录因子结合位点的突变积累源于这些位点错误的修复。因此通常运用基因组元件的突变模式设计在非编码区鉴定潜在的体细胞驱动突变,必须构建准确的背景突变率模型。考虑到这一事实,核苷酸切除修复和与DNA结合的蛋白之间相关性对于理解人类基因修复机制的基本认识有很大帮助,可以促进对突变规模、肿瘤进化和癌症相关体细胞突变的了解。

研究人员表示尽管人体具有良好的自我修复能力,但是当我们持续遭受诸如紫外线和香烟烟雾之类的诱变剂导致的DNA损伤时,我们的基因组中的某些区域并不能得到很好的修复。通过主动地避免接触这些有害的环境因素,我们应当能够让在我们的身体中能够导致癌症的DNA突变产生数量最小化。

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