title: Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung.
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.
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Leng
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Guodong
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Collins
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Thomas
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Carmen S
authors.initials: CS
authors.lastname: Tellez
authors.affiliation: Lung Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Jauregui
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Picchi
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Xiequn
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Juri
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Shantu G
authors.initials: SG
authors.lastname: Amin
authors.affiliation: Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Crowell
authors.affiliation: Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Stidley
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Lung Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Wathelet
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Gilliland
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico. sbelinsk@LRRI.org.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
mesh_terms: D001483:Base Sequence; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008137:Longitudinal Studies; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D008745:Methylation; D008770:Methylnitrosourea / Q000494:pharmacology; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; D006147:Guanine; D008770:Methylnitrosourea; C008449:O-(6)-methylguanine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C113474:UBR1 protein, human; D044767:Ubiquitin-Protein Ligases; D045643:DNA Repair Enzymes