Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung

Cancer Res. 2015 Aug 1;75(15):3108-17. doi: 10.1158/0008-5472.CAN-15-0243. Epub 2015 Jul 16.

Abstract

O(6)-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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Base Sequence
  • Chromosomes, Human, Pair 15 / genetics*
  • DNA Methylation
  • DNA Modification Methylases / genetics
  • DNA Modification Methylases / metabolism*
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism*
  • Epithelial Cells / drug effects
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Guanine / analogs & derivatives
  • Guanine / metabolism
  • Humans
  • Longitudinal Studies
  • Lung Neoplasms / genetics
  • Male
  • Methylation
  • Methylnitrosourea / pharmacology
  • Molecular Sequence Data
  • Polymorphism, Single Nucleotide
  • Smoking / genetics*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / genetics*

Substances

  • Tumor Suppressor Proteins
  • Guanine
  • Methylnitrosourea
  • O-(6)-methylguanine
  • DNA Modification Methylases
  • MGMT protein, human
  • UBR1 protein, human
  • Ubiquitin-Protein Ligases
  • DNA Repair Enzymes