RUI: Interplay between epigenetic methylation and oxidative damage: effects on DNA stability, structure and dynamics.

智力优势：生物体的遗传信息以四种DNA元素的线性聚合物形式存储：鸟嘌呤、胞嘧啶、腺嘌呤和胸腺嘧啶。基因组DNA的化学修饰在自然基因调控和DNA损伤中都起着重要作用。在细胞中，基因活性是通过胞嘧啶的酶修饰（甲基化）来调节的。胞嘧啶修饰率是至关重要的，因为它们的改变会损害细胞功能和生物体的生存。与胞嘧啶的这种修饰不同，它具有调节作用，鸟嘌呤的修饰（氧化）对遗传信息的完整性是有害的。如果不进行修复，这种常见的鸟嘌呤损伤（病变）会导致基因组不稳定和突变。在人类基因组中，胞嘧啶和鸟嘌呤有很多是相邻的（聚类）。已知邻近修饰胞嘧啶的鸟嘌呤损伤的修复受到损害。同样，正常的胞嘧啶修饰率在含有修饰的鸟嘌呤的位点内被改变。这些不利的酶学作用的化学原因尚未确定。其中一个缺失的环节是修饰的鸟嘌呤和胞嘧啶聚集在一起的DNA特征。为了缩小这一差距，该项目旨在利用核磁共振（NMR）技术以及分子动力学模拟，研究鸟嘌呤损伤与修饰胞嘧啶相邻的DNA的基本生物物理学（稳定性，结构和动力学）。这样一项对DNA相关损伤和调控修饰的全面研究将首次进行，开创了基因组稳定性和调控的新研究。更广泛的影响：该项目吸引了西华盛顿大学的学生，这是一所主要的本科院校。学校尽一切努力招收来自少数民族和贫困人口的学生。参与的学生参与现代的跨学科学术研究，涵盖化学、生物、物理和计算机科学等领域，具有重要的科学和教学价值。该项目使学生有机会在实验室中体验全面的学术研究。学生们还以共同作者的身份交流研究结果，这进一步促进了他们的专业发展。为了使更多的学生受益，在这次调查中获得的一些DNA样本将用于西华盛顿大学的教学。总体而言，该项目有助于将研究与教育结合起来，为本科生的工业生涯和博士研究做好准备。

Intellectual Merit: The genetic information in living organisms is stored as linear polymers of four DNA elements: guanine, cytosine, adenine, and thymine. Chemical modifications of genomic DNA have principal roles in both natural gene regulation and DNA damage. In the cell, gene activity is regulated via enzymatic modification of cytosine (methylation). Cytosine modification rates are vital as their alteration can compromise cell function and organism survival. Unlike this modification of cytosine, which serves a regulatory role, modification of guanine (oxidation) is detrimental to the integrity of the genetic information. Left unrepaired, this common type of guanine damage (lesion) can lead to genome instability and mutations. In the human genome, there are many occurrences of cytosine and guanine being adjacent (clustered). Repair of a guanine lesion neighboring a modified cytosine is known to be compromised. Likewise, normal cytosine modification rates are altered within the sites containing a modified guanine. The chemical reasons for these adverse enzymological effects have yet to be determined. One of the missing links is the characterization of DNA with modified guanine and cytosine clustered together. To close this gap, the project aims to investigate the fundamental biophysics (stability, structure and dynamics) of DNA with a guanine lesion adjacent to a modified cytosine, using nuclear magnetic resonance (NMR) techniques along with molecular dynamics simulations. Such a comprehensive study of linked damage and regulatory modifications in DNA will be performed for the first time, pioneering new research in genome stability and regulation.Broader Impacts: The project engages students at Western Washington University, a primarily undergraduate institution. Every effort is made to include students from minority and underprivileged populations. The participating students are involved in modern, inter-disciplinary academic research spanning areas of chemistry, biology, physics and computer science, a combination of principal scientific and instructional value. The project gives the students an early opportunity to experience the full scope of academic research in the lab. The students also communicate the results as co-authors, which further advances their professional development. As a benefit to a wider student body, some of the DNA samples developed during this investigation will be used for classes taught at Western Washington University. Overall, the project helps to integrate research with education and prepare undergraduate students for industry careers and Ph.D. studies.