Chen Siyu, Lees-Miller James P, He Yuan, Lees-Miller Susan P
Department of Molecular Biosciences, Northwestern University, Evanston, IL USA.
Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL USA.
Genome Instab Dis. 2021;2(4):195-210. doi: 10.1007/s42764-021-00047-w. Epub 2021 Jul 23.
DNA-dependent protein kinase catalytic subunit DNA-PKcs/ is the largest serine/threonine protein kinase of the phosphatidyl inositol 3-kinase-like protein kinase (PIKK) family and is the most highly expressed PIKK in human cells. With its DNA-binding partner Ku70/80, DNA-PKcs is required for regulated and efficient repair of ionizing radiation-induced DNA double-strand breaks via the non-homologous end joining (NHEJ) pathway. Loss of DNA-PKcs or other NHEJ factors leads to radiation sensitivity and unrepaired DNA double-strand breaks (DSBs), as well as defects in V(D)J recombination and immune defects. In this review, we highlight the contributions of the late Dr. Carl W. Anderson to the discovery and early characterization of DNA-PK. We furthermore build upon his foundational work to provide recent insights into the structure of NHEJ synaptic complexes, an evolutionarily conserved and functionally important YRPD motif, and the role of DNA-PKcs and its phosphorylation in NHEJ. The combined results identify DNA-PKcs as a master regulator that is activated by its detection of two double-strand DNA ends for a cascade of phosphorylation events that provide specificity and efficiency in assembling the synaptic complex for NHEJ.
DNA依赖蛋白激酶催化亚基（DNA-PKcs）是磷脂酰肌醇3激酶样蛋白激酶（PIKK）家族中最大的丝氨酸/苏氨酸蛋白激酶，也是人类细胞中表达量最高的PIKK。与它的DNA结合伴侣Ku70/80一起，DNA-PKcs是通过非同源末端连接（NHEJ）途径对电离辐射诱导的DNA双链断裂进行有序且高效修复所必需的。DNA-PKcs或其他NHEJ因子的缺失会导致辐射敏感性和未修复的DNA双链断裂（DSB），以及V(D)J重组缺陷和免疫缺陷。在这篇综述中，我们着重介绍已故的卡尔·W·安德森博士对DNA-PK的发现和早期特性描述所做出的贡献。此外，我们在他的基础工作之上，提供对NHEJ突触复合体结构、一个进化上保守且功能重要的YRPD基序，以及DNA-PKcs及其磷酸化在NHEJ中的作用的最新见解。综合结果表明，DNA-PKcs是一种主调节器，它通过检测两个双链DNA末端被激活，引发一系列磷酸化事件，这些事件在为NHEJ组装突触复合体时提供特异性和效率。
