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Functional characterization of RAD52 as a lung cancer susceptibility gene in the 12p13.33 locus. Mol Carcinog 2016 May;55(5):953-63 PMID: 26013599 PMCID: PMC4662629

Pubmed ID

26013599

DOI

10.1002/mc.22334

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.

Author List

Lieberman R, Xiong D, James M, Han Y, Amos CI, Wang L, You M

Authors

Michael James PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Liang Wang MD, PhD Professor in the Pathology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




Scopus

2-s2.0-84930260740   12 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Carcinoma, Squamous Cell
Cell Line, Tumor
Cell Proliferation
Chromosomes, Human, Pair 12
DNA Damage
European Continental Ancestry Group
Gene Amplification
Genetic Predisposition to Disease
Humans
Lung Neoplasms
Mice
Neoplasm Transplantation
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Rad52 DNA Repair and Recombination Protein
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e