title: Functional characterization of RAD52 as a lung cancer susceptibility gene in the 12p13.33 locus.
abstract: Recent genome-wide association studies have identified variations in the recombination repair gene, RAD52, that are associated with increased lung cancer risk, and particularly with the development of lung squamous cell carcinomas (LUSC). As LUSC development is strongly associated with smoking, DNA repair is increased in the lung tissues of smokers, presumably because of ongoing DNA damage from exposure to tobacco smoke. A key player in the DNA damage response, RAD52 plays a role in DNA strand exchange and annealing during homologous recombination (HR) in mammalian cells. In this study, we discovered two cis-expression quantitative trait loci (eQTL) SNPs in the RAD52 gene that are associated with its expression and are also associated with LUSC risk. In addition, we report that amplification of the genomic region 12p13.33, which contains the RAD52 gene, is significantly associated with the development of LUSC in the TCGA database and that somatic overexpression of RAD52 was confirmed to be significant in LUSC tumors from our own patient cohort. Consistent with these genetic findings, we demonstrate that blockade of Rad52 slows cell growth and induces senescence in mouse bronchial epithelial cells. In contrast, overexpression of Rad52 leads to an increased rate of cell proliferation. We show that depletion of Rad52 in mouse lung tumor cells alters cell cycle distribution and increases DNA damage accumulation associated with increased tumor cell death. Our genetic and functional data implicate RAD52 as a significant determinant of risk in the development of LUSC.
authors.affiliation: Department of Pharmacology & Toxicology and Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Rachel
authors.initials: R
authors.lastname: Lieberman
authors.affiliation: Department of Pharmacology & Toxicology and Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Donghai
authors.initials: D
authors.lastname: Xiong
authors.affiliation: Department of Pharmacology & Toxicology and Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Michael
authors.initials: M
authors.lastname: James
authors.affiliation: Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire.
authors.forename: Younghun
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Department of Pathology and Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology & Toxicology and Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Ming
authors.initials: M
authors.lastname: You
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D004249:DNA Damage; D005784:Gene Amplification; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D009368:Neoplasm Transplantation; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics* / Q000378:metabolism*; D044465:White People / Q000235:genetics
chemical_list: C497194:RAD52 protein, human; D051721:Rad52 DNA Repair and Recombination Protein
keywords: DNA damage; cancer susceptibility gene; eQTL; gene amplification; lung cancer; non-small cell lung carcinoma; senescence