Specks Julia, Nieto-Soler Maria, Lopez-Contreras Andres J, Fernandez-Capetillo Oscar
Genomic Instability Group, Spanish National Cancer Research Center (CNIO), C/Melchor Fernandez Almagro, 3, E-28029, Madrid, Spain.
Methods Mol Biol. 2015;1267:413-37. doi: 10.1007/978-1-4939-2297-0_21.
Damaged DNA has a profound impact on mammalian health and overall survival. In addition to being the source of mutations that initiate cancer, the accumulation of toxic amounts of DNA damage can cause severe developmental diseases and accelerate aging. Therefore, understanding how cells respond to DNA damage has become one of the most intense areas of biomedical research in the recent years. However, whereas most mechanistic studies derive from in vitro or in cellulo work, the impact of a given mutation on a living organism is largely unpredictable. For instance, why BRCA1 mutations preferentially lead to breast cancer whereas mutations compromising mismatch repair drive colon cancer is still not understood. In this context, evaluating the specific physiological impact of mutations that compromise genome integrity has become crucial for a better dimensioning of our knowledge. We here describe the various technologies that can be used for modeling mutations in mice and provide a review of the genes and pathways that have been modeled so far in the context of DNA damage responses.
受损的DNA对哺乳动物的健康和整体生存有着深远影响。除了是引发癌症的突变来源外，大量有毒的DNA损伤积累会导致严重的发育疾病并加速衰老。因此，了解细胞如何应对DNA损伤已成为近年来生物医学研究最热门的领域之一。然而，尽管大多数机制研究来自体外或细胞内实验，但特定突变对活体生物的影响在很大程度上是不可预测的。例如，为什么BRCA1突变优先导致乳腺癌，而损害错配修复的突变会引发结肠癌，目前仍不清楚。在这种情况下，评估损害基因组完整性的突变的特定生理影响对于更全面地理解我们的知识变得至关重要。我们在此描述可用于在小鼠中模拟突变的各种技术，并综述迄今为止在DNA损伤反应背景下已被模拟的基因和通路。
