Siyu Chen, James P Lees-Miller, Yuan He, Susan P Lees-Miller
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引用次数: 17
摘要
dna依赖性蛋白激酶催化亚基DNA-PKcs/PRKDC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,是人类细胞中表达量最高的PIKK。DNA- pkcs与其DNA结合伙伴Ku70/80一起,通过非同源末端连接(non-homologous end joining, NHEJ)途径调控和有效修复电离辐射诱导的DNA双链断裂。DNA- pkcs或其他NHEJ因子的缺失导致辐射敏感性和未修复的DNA双链断裂(DSBs),以及V(D)J重组缺陷和免疫缺陷。在这篇综述中,我们强调了已故的卡尔·w·安德森博士对DNA-PK的发现和早期表征的贡献。我们进一步以他的基础工作为基础,提供了对NHEJ突触复合物结构的最新见解,这是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。综合结果确定DNA- pkcs是一个主调节因子,通过检测两条双链DNA末端来激活一系列磷酸化事件,这些磷酸化事件为NHEJ的突触复合体的组装提供了特异性和效率。
Structural insights into the role of DNA-PK as a master regulator in NHEJ.
DNA-dependent protein kinase catalytic subunit DNA-PKcs/PRKDC 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.