Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung
| Autor: | Shuguang Leng, Yushi Liu, Christine A. Stidley, Maria A. Picchi, Shantu Amin, Carmen S. Tellez, Daniel E. Juri, Cynthia L. Thomas, Xiequn Zhang, Leonard B. Collins, Frank D. Gilliland, Marc G. Wathelet, Dhimant Desai, Yong Lin, James A. Swenberg, Guodong Wu, Richard E. Crowell, Andrew R. Jauregui, Steven A. Belinsky |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Cancer Research Methyltransferase Guanine Lung Neoplasms DNA repair Ubiquitin-Protein Ligases Molecular Sequence Data medicine.disease_cause Methylation Polymorphism Single Nucleotide Article chemistry.chemical_compound medicine SNP Humans Genetic Predisposition to Disease Longitudinal Studies Lung cancer Enhancer DNA Modification Methylases neoplasms Chromosomes Human Pair 15 biology Base Sequence Tumor Suppressor Proteins Smoking Epithelial Cells Methylnitrosourea DNA Methylation medicine.disease Molecular biology digestive system diseases Ubiquitin ligase DNA Repair Enzymes Oncology chemistry Gene Expression Regulation biology.protein Female Carcinogenesis DNA Genome-Wide Association Study |
| DOI: | 10.17615/6d2h-1e26 |
| Popis: | O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that protects cells from carcinogenic effects of alkylating agents; however, MGMT is silenced by promoter hypermethylation during carcinogenesis. A single-nucleotide polymorphism (SNP) in an enhancer in the MGMT promoter was previously identified to be highly significantly associated with risk for MGMT methylation in lung cancer and sputum from smokers. To further genetic investigations, a genome-wide association and replication study was conducted in two smoker cohorts to identify novel loci for MGMT methylation in sputum that were independent of the MGMT enhancer polymorphism. Two novel trans-acting loci (15q15.2 and 17q24.3) that were identified acted together with the enhancer SNP to empower risk prediction for MGMT methylation. We found that the predisposition to MGMT methylation arising from the 15q15.2 locus involved regulation of the ubiquitin protein ligase E3 component UBR1. UBR1 attenuation reduced turnover of MGMT protein and increased repair of O6-methylguanine in nitrosomethylurea-treated human bronchial epithelial cells, while also reducing MGMT promoter activity and abolishing MGMT induction. Overall, our results substantiate reduced gene transcription as a major mechanism for predisposition to MGMT methylation in the lungs of smokers, and support the importance of UBR1 in regulating MGMT homeostasis and DNA repair of alkylated DNA adducts in cells. Cancer Res; 75(15); 3108–17. ©2015 AACR. |
| Databáze: | OpenAIRE |
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