Abstract 5103: Analysis of the role of “ATM” through “omics” analysis

Abstract

Abstract The human genetic disease, ataxia-telangiectasia (AT) is characterized by exquisite radiation sensitivity, neurological degeneration, immune deficiencies, genetic instability and predisposition to cancer. Furthermore, cells from patients with AT show disruption of the DNA damage response (DDR), a global signaling network that senses damage and coordinates cellular responses that include cell cycle regulation, transcription, DNA repair processes and apoptosis. Previously, AT5BIVA cells have been was established by SV40 immortalization of fibroblasts derived from an AT group D patient. We derived ATCL8 cells line was then derived by transfecting AT5BIVA with a vector carrying expressing the full- length wild type ATM. ATCL8 cells are and was found to be less sensitive to radiation resistant (D0=1.7 Gy) as compared tothan are the parental cell line AT5BIVA cells (D0=0.7 Gy). We have used a systems approach to understand compare the baseline changes that occur at the genomics, proteomics and metabolomic levels in these two near isogenic cell lines and integrate the information to understand the correlation. The. mMicroarray analysies wereas carried performed out to compare investigate basal level changes in gene expression. between AT5BIVA and ATCL8. The p Proteomics analysies for the same system was donewere performed using a 2-D gels and mass spectrometry approach. Finally, metabolomic profilesing was performed were obtained using UPLC-ESI-TOF mass spectrometry followed by multivariate data analysis using (SIMCA-P and random forest) software. The mMetabolites which were found observed to be significantly different in ATCL8 as compared to AT5BIVA were then subjected to functional pathway analysies using the ingenuity software. The proteomics and the microarray data were then scored for the presence of proteins and genes which were a part of the predominant signaling pathways in the two cell lines as determined by metabolomic analysis. The model system used in this study involves studyingof basal level changes in expression resulting from perturbations in a single gene and our results demonstrate the feasibility of such an the approach to correlate the changes found at all three levels of expression. The findings will be discussed in the context of the “AT” phenotype will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5103.