Altered Kinetics of Non-Homologous End Joining Mediated DNA Repair in Mouse Models of Aging and Leukemia

dc.contributor.authorPuthiyaveetil Abdulkader, Abdul Gafooren
dc.contributor.committeechairCaudell, David L.en
dc.contributor.committeememberAhmed, S. Ansaren
dc.contributor.committeememberReilly, Christopher M.en
dc.contributor.committeememberMitchell, Kimberly J.en
dc.contributor.committeememberPardee, Timothy S.en
dc.contributor.departmentVeterinary Medical Sciencesen
dc.date.accessioned2017-04-06T15:44:00Zen
dc.date.adate2012-11-09en
dc.date.available2017-04-06T15:44:00Zen
dc.date.issued2012-09-25en
dc.date.rdate2016-10-17en
dc.date.sdate2012-09-30en
dc.description.abstractDNA encodes the genetic instructions for the development and function of organisms and hence maintaining genomic integrity is essential for the propagation of life. However, DNA molecules are under constant threat of metabolic and environmental insults resulting in DNA damages including DNA double strand breaks (DSB), which are considered as a serious threat to cell survival. The majority of these DSB are repaired by Non-homologous end joining (NHEJ). Unrepaired DSB can lead to genomic instability resulting in cell cycle arrest, apoptosis, and mutations. Thus, delineating this DNA repair process is important in understanding the molecular mechanisms of aging and malignant progression. B lymphocytes undergo physiological DNA breaks and NHEJ-mediated DNA repair during their bone marrow differentiation and peripheral class switch recombination (CSR), thus lending them as a good model system in which to delineate the DNA repair mechanisms. To determine the effect of aging on NHEJ, B lymphocytes from old mice were analyzed. The results showed compromised DNA repair in cells from old mice compared to cells from adult mice. These results suggest that NHEJ is compromised during aging and might play critical roles in the aging process and age-associated conditions. To delineate the role of a CT in regulating the immune system, transgenic mice expressing NUP98-HOXD13 (NHD13) were analyzed for B lymphocyte differentiation, peripheral development, CSR, and antibody production. The results showed impaired B cell development and antibody production, which worsened with antigenic stimulation, suggesting the role of NHD13 in immune regulation. These studies explored the possibility of altered NHEJ-mediated DNA repair as a contributing reason for aging process and age-associated conditions. Also, the results from NHD13 study suggested that a primary CT can result in impaired NHEJ and regulate immune cell development and function. Furthermore, the results pointed to the possibility that a primary CT may lead to secondary mutations through altered NHEJ. Thus, these studies shed insight into the molecular mechanisms of altered NHEJ and may help in developing preventive or therapeutic strategies against accumulation of DNA damage, aging process and secondary mutations.en
dc.description.degreePh. D.en
dc.identifier.otheretd-09302012-150514en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-09302012-150514/en
dc.identifier.urihttp://hdl.handle.net/10919/77233en
dc.language.isoen_USen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectalternative end joiningen
dc.subjectnon-homologous end joiningen
dc.subjectclass switch recombinationen
dc.subjectAgingen
dc.subjectB lymphocytesen
dc.subjectchromosomal translocationen
dc.titleAltered Kinetics of Non-Homologous End Joining Mediated DNA Repair in Mouse Models of Aging and Leukemiaen
dc.typeDissertationen
dc.type.dcmitypeTexten
thesis.degree.disciplineVeterinary Medical Sciencesen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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