Role for Artemis nuclease in the repair of radiation-induced DNA double strand breaks by alternative end joining |
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| Affiliation: | 1. Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, Essen, Germany;2. Graduate School of Nanobioscience and Advanced Medical Research Center, Yokohama City University, Yokohama, Japan;1. Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, SP, Brazil;2. Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil;1. Department of Genetics, University of North Carolina, Chapel Hill, Genetic Medicine Building 5061, CB#7264, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA;2. Curriculum for Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA;3. Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA;4. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA;1. Stowers Institute for Medical Research, Kansas City, MO 64110, USA;2. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA;1. Department of Pharmacology and Toxicology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States;2. Life Sciences Division, Lawrence Berkeley Laboratory, Berkeley, CA 94720, United States;3. Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, United States;4. Department of Chemistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States;1. Department of Engineering and Applied Physics, University of Science and Technology of China, Hefei, Anhui, 230026, China;2. Institute of Plasma Physics, Chinese Academy of Sciences, Hefei, Anhui, 230031, China;3. Department of Nuclear Engineering, Seoul National University, Seoul 151-742, South Korea |
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| Abstract: | Exposure of cells to ionizing radiation or radiomimetic drugs generates DNA double-strand breaks that are processed either by homologous recombination repair (HRR), or by canonical, DNA-PKcs-dependent non-homologous end-joining (C-NHEJ). Chemical or genetic inactivation of factors involved in C-NHEJ or HRR, but also their local failure in repair proficient cells, promotes an alternative, error-prone end-joining pathway that serves as backup (A-EJ). There is evidence for the involvement of Artemis endonuclease, a protein deficient in a human radiosensitivity syndrome associated with severe immunodeficiency (RS-SCID), in the processing of subsets of DSBs by HRR or C-NHEJ. It is thought that within HRR or C-NHEJ Artemis processes DNA termini at complex DSBs. Whether Artemis has a role in A-EJ remains unknown. Here, we analyze using pulsed-field gel electrophoresis (PFGE) and specialized reporter assays, DSB repair in wild-type pre-B NALM-6 lymphocytes, as well as in their Artemis−/−, DNA ligase 4−/− (LIG4−/−), and LIG4−/−/Artemis−/− double mutant counterparts, under conditions allowing evaluation of A-EJ. Our results substantiate the suggested roles of Artemis in C-NHEJ and HRR, but also demonstrate a role for the protein in A-EJ that is confirmed in Artemis deficient normal human fibroblasts. We conclude that Artemis is a nuclease participating in DSB repair by all major repair pathways. |
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| Keywords: | Non-homologous end-joining (NHEJ) Alternative end joining (A-EJ) DNA double-strand breaks (DSBs) Artemis nuclease Ionizing radiation (IR) |
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