Functional characterization of RAD52 as a lung cancer susceptibility gene in the 12p13.33 locus

Rachel Lieberman, Donghai Xiong, Michael James, Younghun Han, Christopher I. Amos, Liang Wang, Ming You

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)953-963
Number of pages11
JournalMolecular Carcinogenesis
Volume55
Issue number5
DOIs
StatePublished - May 1 2016

Keywords

  • Cancer susceptibility gene
  • DNA damage
  • EQTL
  • Gene amplification
  • Lung cancer
  • Non-small cell lung carcinoma
  • Senescence

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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