The mechanism of ATP-dependent nucleosome remodeling -- Dissection of the function of important protein domains and nucleosomal epitopes

在所有真核细胞中，核小体重塑酶沿着DNA重新定位核小体。因此，它们使受核小体保护的DNA可接近其他因子。核小体重塑影响依赖于DNA可及性的基本遗传过程，如转录、复制、重组和DNA修复。因此，几种重塑酶与人类疾病有关并不奇怪。所有的重塑酶都含有一个ATP酶的“马达”结构域，可以自主地重新定位核小体。其他的辅助蛋白质结构域进化来调节这个运动模块，并将反应转向不同的结果。在分子水平上理解这种调节是揭示整体重塑机制的关键。在我们的工作计划中，我们计划解剖一个复杂的调控网络赋予特定的重塑结构域与核小体表位。将采用定量生物化学和生物物理方法以及创新的结构方法。我们希望深入了解这些迷人的分子机器的内部运作，我们可能会发现适用于更复杂的重塑酶的原理。

Nucleosome remodeling enzymes reposition nucleosomes along DNA in all eukaryotic cells. They thereby render the DNA that is protected by the nucleosome accessible to other factors. Nucleosome remodeling affects fundamental genetic processes that rely on accessibility of DNA, such as transcription, replication, recombination and DNA repair. It is therefore not surprising that several remodeling enzymes have been implicated in human diseases. All remodeling enzymes contain an ATPase 'motor' domain that can autonomously reposition nucleosomes. Other, accessory protein domains evolved to regulate this motor module and steer the reaction towards different outcomes. Understanding this regulation on the molecular level holds the key to uncover the overall remodeling mechanism. In our work program we plan to dissect an intricate regulatory network imparted by specific remodeler domains in conjunction with nucleosomal epitopes. Quantitative biochemical and biophysical methods and innovative structural approaches will be employed. We hope to obtain insight into the inner workings of these fascinating molecular machines, and we may discover principles that are applicable to more complex remodeling enzymes.