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DNA double-strand breaks occur as part of the physiologic development of the immune repertoire in B and T lymphocytes. We study the manner in which these breaks are generated in a process called V(D)J recombination. Defects in the normal enzymes that generate these breaks can result in inherited forms of human severe combined immune deficiency (SCID). We study the biochemistry of how these proteins function, and we study how mutations in them result in SCID. Once DNA breaks are generated, they must be repaired. All cells of the body possess the ability to repair double-strand DNA breaks because all cells must deal with pathologic breaks in DNA that arise due to external radiation or due to free radicals of oxidative metabolism. The major pathway for repairing double-strand breaks in mammalian cells is called nonhomologous DNA end joining (NHEJ). If this pathway is defective in lymphocytes, then the breaks generated can not be repaired. Such defects also result in SCID. If the NHEJ pathway is defectve in all cells of the body, not only is the immune system affected, but the entire body is extremely vulnerable to ionizing radiation. Our laboratory has made substantial progress in defining proteins important in the NHEJ pathway. The first protein in the NHEJ pathway, Ku, binds at the broken DNA ends. The Artemis:DNA-PKcs complex is recruited to the DNA end by Ku. This binding activates the protein kinase activity of DNA-PKcs, which then phosphorylates Artemis and makes the Artemis:DNA-PKcs complex a potent nuclease for trimming DNA ends. Polymerase mu and lambda fill-in gaps, and polymerase mu can add nucleotides template-indepenently, like TdT. Finally, DNA ligase IV, XRCC4, and XLF form the ligation complex which ligates the double-strand break. We are interested in how all of these proteins carry out their functions and how their structure is important for this, and we are interested in identifying any other proteins that might be in th is pathway. We are also interested in how chromatin structure affects these proteins as they repair DNA breaks. The process of NHEJ is intrinsically imprecise. We suspect that this imprecision may contribute to the aging of somatic cells over time as well as to cancer. We are currently investigating this possibility using cell culture models, animal models, and analysis of human cells. Identification of inhibitors of NHEJ would be useful in cancer therapy and in improving gene targeting in human stem cells, and hence, we are trying to identify inhibitors of the pathway and individual components.
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BMC research notesno. 1 (2023): 66-6
Progress in Biophysics and Molecular Biology (2023): 105-119
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