Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 980 W. Walnut St., Indianapolis, IN 46202, USA.
Antioxid Redox Signal. 2011 Jun 15;14(12):2531-43. doi: 10.1089/ars.2010.3368. Epub 2010 Dec 2.
DNA double-strand breaks (DSB), particularly those induced by ionizing radiation (IR), are complex lesions that can be cytotoxic if not properly repaired. IR-induced DSB often have DNA termini modifications, including thymine glycols, ring fragmentation, 3'-phosphoglycolates, 5'-hydroxyl groups, and abasic sites. Nonhomologous end joining (NHEJ) is a major pathway responsible for the repair of these complex breaks. Proteins involved in NHEJ include the Ku 70/80 heterodimer, DNA-PKcs, processing proteins including Artemis and DNA polymerases μ and λ, XRCC4, DNA ligase IV, and XLF. We will discuss the role of the physical and functional interactions of DNA-PK as a result of activation, with an emphasis on DNA structure, chemistry, and sequence. With the diversity of IR induced DSB, it is becoming increasingly clear that multiple DNA processing enzymes are likely necessary for effective repair of a break. We will explore the roles of several important processing enzymes, with a focus on the nuclease Artemis and its role in processing diverse DSB. The effect of DNA termini on both DNA-PK and Artemis activity will be analyzed from a structural and biochemical view.
DNA 双链断裂 (DSB)，特别是由电离辐射 (IR) 诱导的 DSB，是复杂的损伤，如果不能正确修复，可能具有细胞毒性。IR 诱导的 DSB 通常会对 DNA 末端进行修饰，包括胸腺嘧啶二醇、环断裂、3'-磷酸甘油酸、5'-羟基和无碱基位点。非同源末端连接 (NHEJ) 是修复这些复杂断裂的主要途径。参与 NHEJ 的蛋白包括 Ku70/80 异二聚体、DNA-PKcs、包括 Artemis 和 DNA 聚合酶 μ 和 λ、XRCC4、DNA 连接酶 IV 和 XLF 在内的加工蛋白。我们将讨论 DNA-PK 由于激活而产生的物理和功能相互作用的作用，重点是 DNA 结构、化学和序列。随着 IR 诱导的 DSB 的多样性不断增加，越来越明显的是，有效的修复断裂可能需要多种 DNA 加工酶。我们将探讨几种重要的加工酶的作用，重点是核酸酶 Artemis 及其在处理各种 DSB 中的作用。将从结构和生化角度分析 DNA 末端对 DNA-PK 和 Artemis 活性的影响。
