Implication of a chromosome 15q15.2 locus in regulating UBR1 and predisposing smokers to MGMT methylation in lung

Shuguang Leng, Guodong Wu, Leonard B. Collins, Cynthia L. Thomas, Carmen S. Tellez, Andrew R. Jauregui, Maria A. Picchi, Xiequn Zhang, Daniel E. Juri, Dhimant Desai, Shantu G. Amin, Richard E. Crowell, Christine A. Stidley, Yushi Liu, James A. Swenberg, Yong Lin, Marc G. Wathelet, Frank D. Gilliland, Steven A. Belinsky

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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 forMGMTmethylation 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.

Original languageEnglish (US)
Pages (from-to)3108-3117
Number of pages10
JournalCancer Research
Volume75
Issue number15
DOIs
Publication statusPublished - Aug 1 2015

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Leng, S., Wu, G., Collins, L. B., Thomas, C. L., Tellez, C. S., Jauregui, A. R., ... Belinsky, S. A. (2015). Implication of a chromosome 15q15.2 locus in regulating UBR1 and predisposing smokers to MGMT methylation in lung. Cancer Research, 75(15), 3108-3117. https://doi.org/10.1158/0008-5472.CAN-15-0243