Coordinating Translesion DNA Synthesis Opposite Damaged DNA

生物有机体经常被要求防止和/或修复基因组DNA的损伤。共价 遗传物质的修饰与导致细胞功能障碍的过程密切相关。 已经进化出几种机制来防止对DNA的破坏。一旦损伤发生，细胞可能会 用一系列修复途径来应对，这些修复途径可以从基因组中物理地移除损伤。如果 DNA的修饰部分在细胞分裂之前不会被移除，然后复制基因的机械 物质，即复制体，会受到破坏，这往往会抑制准确的DNA复制 事件。复制体的中心是一种名为DNA聚合酶的酶。这些酶的作用就是 在确定病变旁路事件是否准确或具有突变性方面起着重要作用。 在生命的每个细胞中都有几种类型的DNA聚合酶。一些DNA 聚合酶在整个进化过程中一直被保留下来，因为它们是一种极其准确和集中的 沃森-克里克碱基对的合成方法。这些所谓的复制DNA聚合酶通常较少 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 当遇到损伤时复制分叉，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射线结晶学和 氢-氚交换质谱学将与功能动力学分析和 细胞研究，以确定专门的DNA聚合酶如何与Werner相互作用 受损DNA搭桥过程中的综合征蛋白。沃纳综合征的特征是过早衰老。 和基因组的不稳定性。了解复制我们基因组的酶是如何工作的 遇到DNA损伤是理解为什么某些化学物质有毒，如何致癌的重要组成部分 发展，甚至与我们为什么变老有关。我们研究的目标是回答与以下问题相关的问题 不同类型的“DNA制造”酶如何发挥作用来维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.