In Vitro Expression Levels of Cell-Cycle Checkpoint Proteins Are Associated with Cellular DNA Repair Capacity in Peripheral Blood Lymphocytes: A Multivariate Analysis

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• 作者：You-Hong Fan ; Zhibin Hu ; Chunying Li ; Li-E Wang ; Zhaozheng Guo ; Yawei Qiao ; Li Zhang ; Wei Zhang ; Li Mao ; Qingyi Wei
• 刊名：Journal of Proteome Research
• 出版年：2007
• 出版时间：April 2007
• 年：2007
• 卷：6
• 期：4
• 页码：1560 - 1567
• 全文大小：400K
• 年卷期：v.6,no.4(April 2007)
• ISSN：1535-3907

文摘

DNA repair should occur after cells sense DNA damage signals and undergo cell-cycle arrest to providesufficient time for DNA repair, and suboptimal DNA repair capacity (DRC) in peripheral lymphocyteshas been suggested as a cancer susceptibility marker. Numerous studies showed a functional linkbetween DNA damage sensing, cell-cycle checkpoint, and DNA repair. We hypothesized that in vitrocell-cycle checkpoint-related protein expression levels in stimulated lymphocytes predict DRC levels.To test this hypothesis, we performed the host-cell reactivation assay for DRC by transfecting stimulatedperipheral blood lymphocytes from 120 normal donors with transient expression plasmids damagedby benzo[a]pyrene diol epoxide (BPDE). The same cells were assessed for protein expression inductionof eight cell-cycle checkpoint-related genes using the reverse-phase protein lysate microarray assay.In multivariate linear regression analysis adjusting for age, sex, blastogenic rate, and sample storageduration, the association between DRC and expression levels of cell-cycle checkpoint-related proteinsinduced by BPDE-adducts was statistically significant for p27, CCND1, ATM, and MDM2 (P = 0.00, 0.03,0.03, and 0.03, respectively), borderline for p73 and p21 (P = 0.07 and 0.09, respectively), but not forp53 and p16 (P = 0.13 and 0.18, respectively). Because the relative expression levels of all these eightproteins were highly correlated, we further performed the principal component analysis and identifiedATM as the most important predictor of DRC, followed by MDM2 and p27. Our results providepopulation-based in vitro evidence demonstrating that cell-cycle checkpoint-related proteins playessential roles in regulating DNA repair, at least in unaffected human peripheral blood lymphocytes.Further studies are warranted to investigate the role of interindividual variation in the expression levelsof these proteins in cancer susceptibility.