Post-transcriptional control of DNA damage responses

我们的脱氧核糖核酸（DNA）不断暴露在破坏我们遗传信息完整性的有害物质中。人类DNA包含近3万个基因，这些基因提供了生产生命所需的所有蛋白质的全套指令。我们的DNA是在细胞核中发现的，而蛋白质是在核糖体中制造的，核糖体在细胞质中物理分离。信使核糖核酸（mrna）用于将遗传信息从我们的基因（DNA）转移到细胞质中的核糖体中进行翻译（蛋白质合成）。mRNA的生命是复杂的。在产生的过程中，它会经过大量的加工以去除不需要编码蛋白质的中间序列（内含子）。此外，mrna的末端被修饰以保护它们，它们被蛋白质包裹，帮助它们到达核糖体。制造mrna的基因转录是必需的，但肯定不足以调节蛋白质的产生。最近的证据（包括我实验室的一些工作）表明，许多mrna被分类、降解，不能作为质量控制的手段离开细胞核。我们发现DNA损伤反应会影响这些分子遗传决定。我们建议使用最先进的功能基因组方法研究暴露于DNA损伤的细胞中RNA加工步骤（从DNA到蛋白质）是如何改变的。我们的工作有望为我们应对来自内部和外部环境的持续DNA损伤的方式提供重要的见解。

Our deoxyribonucleic acid (DNA) is constantly exposed to damaging agents that challenge the integrity of our genetic information. Human DNA contains almost 30 000 genes that provide the full set of instructions to produce all of the proteins required for life. Our DNA is found in the nucleus while proteins are made in ribosomes that are physically separated in the cytoplasm of the cell. Messenger Ribonucleic acids (mRNAs) are used to transfer the genetic information from our genes (DNA) to the ribosomes in the cytoplasm for translation (protein synthesis). The life of the mRNA is complex. As it is produced, it undergoes extensive processing to remove intervening sequences (introns) that are not required to encode proteins. In addition, the ends of the mRNAs are modified to protect them and they become coated with proteins that help them on their journey to ribosomes. The transcription of genes to make mRNAs is required but is certainly not sufficient to regulate protein production. Recent evidence, including some work from my laboratory, indicates that many mRNAs are triaged, degraded and fail to exit the nucleus as a means of quality control. We find that DNA damage responses affect these molecular genetic decisions. We propose to study how the RNA processing steps (from DNA to protein) are changed in cells that are exposed to DNA damage using state-of-the-art functional genomic approaches. Our work promises to provide important insight into the ways we deal with the constant onslaught of DNA damage coming from our internal and external environments.