Coordinating Translesion DNA Synthesis Opposite Damaged DNA

生物有机体不断需要防止和/或修复对基因组DNA的损伤。共价 遗传物质的改变与导致细胞功能障碍的过程密切相关。 有几种机制已经进化出来，以防止对DNA的损伤。一旦损伤发生， 通过一系列修复途径将损伤从基因组中移除。如果 在细胞分裂之前，DNA的修饰部分并没有被移除，然后复制基因的机器被移除。 复制体这种物质会受到损伤，这通常会抑制DNA的精确复制 事件复制体的中心是一种叫做DNA聚合酶的酶。这些酶的作用 在确定病变旁路事件是准确的还是致突变的方面具有重要作用。 在生命的每个细胞中都有几种类型的DNA聚合酶。一些DNA 聚合酶在进化过程中一直被保留下来，因为它们是一种非常精确和集中的酶。 合成沃森-克里克碱基对的方法。这些所谓的复制型DNA聚合酶通常 能够绕过DNA加合物。其他专门的聚合酶具有病变旁路能力，可以帮助 复制叉，但这两种类型的DNA聚合酶是如何协调的， 对DNA损伤的反应尚不清楚。结构方法，包括X射线晶体学和 氢-氘交换质谱法将与功能动力学分析相结合， 细胞研究，以确定专门的DNA聚合酶如何与沃纳 绕过受损DNA期间的综合症蛋白。沃纳综合征的特征是过早衰老 和基因组不稳定性。了解复制我们基因组的酶如何发挥作用， 遭遇DNA损伤是理解为什么某些化学物质有毒的重要组成部分， 发展，甚至与我们为什么衰老有关。我们的研究目标是回答与以下方面有关的问题： 不同类型的“DNA制造”酶如何发挥作用以保持我们遗传物质的完整性。

Biological organisms are constantly required to prevent and/or repair damage to genomic DNA. Covalent modification ofthe genetic material is intimately related to processes that contribute to cellular dysfunction. Several mechanisms have evolved to prevent damage to DNA. Once the damage occurs the cell may respond with an arsenal of repair pathways that physically remove the lesions from the genome. If the modified portions of DNA are not removed prior to cell division then the machinery that copies the genetic material, the replisome, will encounter the damage, which often proves inhibitory to accurate DNA replication events. Central to the replisome is an enzyme called a DNA polymerase. The actions of these enzymes play an important role in determining whether a lesion bypass event is accurate or mutagenic. There are several types of DNA polymerase in every cell across the spectrum of life. Some DNA polymerases have been retained throughout evolution because they are an extremely accurate and focused means of synthesizing Watson-Crick base pairs. These so-called replicative DNA polymerases are often less able to bypass DNA adducts. Other specialized polymerases possess lesion bypass abilities that can aid the replication fork when it encounters damage, but how these two types of DNA polymerases are coordinated in response to DNA damage remains unclear. Structural approaches including x-ray crystallography and hydrogen-deuterium exchange mass spectrometry will be combined with functional kinetic analysis and cellular studies in an effort to determine how specialized DNA polymerases interact with the Werner syndrome protein during bypass of damaged DNA. Werner syndrome is characterized by premature aging and genomic instability. Understanding how the enzymes that copy our genome function when they encounter DNA damage is an important part of understandig why certain chemicals are toxic, how cancer develops, and even relates to why we age. The goals of our research seek to answer questions related to how different types of "DNA making" enzymes function to maintain the integrity of our genetic material.