Artemis, Goddess of the hunt
and protector of children.
Immunity, DNA Repair and Cancer
It may not be immediately apparent how DNA repair, immunity, and cancer are related. In our laboratory we have come to theses seemingly different topics by studying the enzymes of human DNA repair. As it turns out, the genes/enzymes essential for repairing DNA are also essential for human immunity. This same set of important genes also indirectly impact both the development of cancer and its treatment. We initially focused much of our effort on understanding the biochemical capabilities and cellular functions of enzymes that have key functions in tthe repair of DNA breaks in cells. Our work has focused on the particular subset of protiens that specifically repair DNA double-strand breaks in human cells, the non-homologous end joining (NHEJ) pathway of repair. The set of proteins that are essential for NHEJ are also required for a specific programmed genetic rearrangement that occurs in white blood cells and is essential for developing an immune system. This process is called V(D)J recombination and individuals defective in some of the genes needed for V(D)J recombination are afflicted with both severe combined immunodeficiency (SCID) and are hyper-sensitive to radiation and chemotherapies because they are also defective in DNA repair. Mutations in the Artemis gene are one such example, and defects in this gene cause a radiation sensitive form of SCID, which poses particularly difficult challenges for treatment of these patients.
In short, defects in NHEJ cause problems with DNA repair which can lead to mutations and cancer. Cancer treatments such as radiation therapy are based on killing cells by causing DNA breaks. Therefore, individuals with defects effecting NHEJ are hyper-sensitivie to radiation and more prone to developing cancer. As if that were not enough, people with defects in these genes also cannot carry out V(D)J recombination and therefore have effectively no immune system (Bubble Boy disease). Bone marrow transplantation in the first year of life if the only long-term treatment for SCID children. Of the half-dozen or so genetic defects that cause SCID, some cause extreme radiation sensitivity and others do not. The problem lies in that there is often no practical way to tell the difference between sensitive and non-sensitive SCID children. Bone marrow transplantation typically involves pre-treatment with radiation or chemicals to kill the defective marrow and create space for the transplanted marrow to grow and engraft. Successful bone marrow transplantation allows the patient to live a relatively normal life as the transplant gives rise to an essentially normal immune system. Transplantation is very effective therapy for those SCID children who are not hypersensitive to radiation, however for those who are hypersensitive, these treatments are frequently fatal. A considerable proportion of our efforts have been directed at understanding the basic functions of NHEJ proteins in human cells. We have more recently focused our efforts on the above problem, namely to develop technologies needed to identify radiation sensitivity in SCID and cancer patients. The ability to detect radiation sensitivity in the laboratory has been available for decades, however no practical method to do this in a clinical setting has been developed. We are currently focused on applying the knowledge we have gained about the basic function of NHEJ proteins in human DNA repair and immunity to develop a reliable method to detect hypersensitivity to radiation in cancer and SCID patients proir to the prescription of radiation and chemotherapies.
Our Relevant Publications:
. 2011 Aug;39(15):6500-10. Epub 2011 Apr 29.
Langland GT, Yannone SM, Langland RA, Nakao A, Guan Y, Long SB, Vonguyen L, Chen DJ, Gray JW, Chen F.
Oncol Rep. 2010 Apr;23(4):1021-6.
Xiao Z, Dunn E, Singh K, Khan IS, Yannone SM, Cowan MJ.
Biol Blood Marrow Transplant. 2009 Jan;15(1):1-11.
Xiao Z, Yannone SM, Dunn E, Cowan MJ.
Eur J Hum Genet. 2009 Feb;17(2):205-12. Epub 2008 Aug 13.
Yannone SM, Khan IS, Zhou RZ, Zhou T, Valerie K, Povirk LF.
Nucleic Acids Res. 2008 Jun;36(10):3354-65. Epub 2008 Apr 25.
Povirk LF, Zhou T, Zhou R, Cowan MJ, Yannone SM.
J Biol Chem. 2007 Feb 9;282(6):3547-58. Epub 2006 Nov 22.
Jones KR, Gewirtz DA, Yannone SM, Zhou S, Schatz DG, Valerie K, Povirk LF.
Mol Cancer Ther. 2005 Oct;4(10):1541-7.
Wang J, Pluth JM, Cooper PK, Cowan MJ, Chen DJ, Yannone SM.
DNA Repair (Amst). 2005 May 2;4(5):556-70.
Li L, Salido E, Zhou Y, Bhattacharyya S, Yannone SM, Dunn E, Meneses J, Feeney AJ, Cowan MJ.
J Immunol. 2005 Feb 15;174(4):2420-8.
Hart LS, Yannone SM, Naczki C, Orlando JS, Waters SB, Akman SA, Chen DJ, Ornelles D, Koumenis C.
J Biol Chem. 2005 Jan 14;280(2):1474-81. Epub 2004 Oct 26.
Przewloka MR, Pardington PE, Yannone SM, Chen DJ, Cary RB.
Mol Biol Cell. 2003 Feb;14(2):685-97.
Lee JW, Yannone SM, Chen DJ, Povirk LF.
Cancer Res. 2003 Jan 1;63(1):22-4.
Hsu HL, Yannone SM, Chen DJ.
DNA Repair (Amst). 2002 Mar 28;1(3):225-35.
Hashimoto M, Donald CD, Yannone SM, Chen DJ, Roy R, Kow YW.
J Biol Chem. 2001 Apr 20;276(16):12827-31. Epub 2001 Jan 25.
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