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). 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.

Human somatic cells deficient for RAD52 are impaired for viral integration and compromised for most aspects of homology-directed repair

“…Moreover, although it was not evident in our data set (Fig. 6G) the overexpression of RAD52 has been shown to be associated with lung squamous cell carcinomas genesis and progression [85]. Lastly, the relative overexpression of RAD52 was also shown to lead to earlier mortality in a mouse model genetically engineered to be predisposed to colorectal carcinomas [43].…”

Molecular Evolution Patterns in Metastatic Lymph Nodes Reflect the Differential Treatment Response of Advanced Primary Lung Cancer

“…12p13.33 amplification appeared in all the lymph nodes and in the primary tumor of this patient. A recent study reported that the recombination repair gene RAD52, within the 12p13.33 region, is associated with the risk of lung squamous cell carcinoma development (31). The expression level of genes belonging to the targetable PI3K/RTK/RAS oncogenic pathway were observed to be above background expression levels of the TCGA squamous cell carcinoma cohort (n ¼ 495; Supplementary Fig.…”

Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks

“…A role for Rad52 in BIR can explain why its depletion in cells with DRS leads to increased DNA damage (Wray et al., 2008, Murfuni et al., 2013, Galanos et al., 2016; Figures 3A and 3B), why the RAD52 gene is amplified in human cancers, and why its inactivation curtails cancer development (Treuner et al., 2004, Cramer-Morales et al., 2013, Lieberman et al., 2016; Figure 4). BIR also mediates DNA repair synthesis in mitosis (Minocherhomji et al., 2015), and it is noteworthy that Rad52 is essential also in this context (Bhowmick et al., 2016).…”