Coordination of DNA-PK activation and nuclease processing of DNA termini in NHEJ.
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.
Pawelczak
Katherine S
KS
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 980 W. Walnut St., Indianapolis, IN 46202, USA.
Bennett
Sara M
SM
Turchi
John J
JJ
D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism*; D004789:Enzyme Activation; D000072200:Ku Autoantigen; D009687:Nuclear Proteins / Q000378:metabolism
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D004247:DNA; D051747:DNA-Activated Protein Kinase; C426344:DCLRE1C protein, human; D004720:Endonucleases; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen