Abstract
Regions of acute and chronic hypoxia exist within solid tumors and can lead to increased rates of mutagenesis and/or altered DNA damage and repair protein expression. Base excision repair (BER) is responsible for resolving small, non-helix-distorting lesions from the genome that potentially cause mutations by mispairing or promoting DNA breaks during replication. Germline and somatic mutations in BER genes, such as MutY Homolog (MUTYH/MYH) and DNA-directed polymerase (POLB), are associated with increased risk of colorectal cancer. However, very little is known about the expression and function of BER proteins under hypoxic stress. Using conditions of chronic hypoxia, decreased expression of BER proteins was observed because of a mechanism involving suppressed BER protein synthesis in multiple colorectal cancer cell lines. Functional BER was impaired as determined by MYH- and 8-oxoguanine (OGG1)-specific glycosylase assays. A formamidopyrimidine-DNA glycosylase (Fpg) Comet assay revealed elevated residual DNA base damage in hypoxic cells 24 hours after H2O2 treatment as compared with normoxic controls. Similarly, high-performance liquid chromatography analysis demonstrated that 8-oxo-2'-deoxyguanosine lesions were elevated in hypoxic cells 3 and 24 hours after potassium bromate (KBrO3) treatment when compared with aerobic cells. Correspondingly, decreased clonogenic survival was observed following exposure to the DNA base damaging agents H2O2 and MMS, but not to the microtubule interfering agent paclitaxel. Thus, a persistent downregulation of BER components by the microenvironment modifies and facilitates a mutator phenotype, driving genetic instability and cancer progression. Aberrant BER is a contributing factor for the observed genetic instability in hypoxic tumor cells.
Highlights
Hypoxia is a common characteristic of solid tumors and is associated with decreased disease-free survival for many cancers, including colorectal cancer [1,2,3,4,5,6,7,8,9]
Suppression of mRNA translation under hypoxia is controlled through at least two distinct pathways; first by PERK-mediated phosphorylation of eIF2a which is required for the recruitment of aminoacylated tRNA, and second by disruption of the mRNA capbinding complex, eIF4F [28]
We provide the first report of hypoxia-mediated suppression of Base excision repair (BER) protein expression and function in colorectal cancer
Summary
Hypoxia is a common characteristic of solid tumors and is associated with decreased disease-free survival for many cancers, including colorectal cancer [1,2,3,4,5,6,7,8,9]. Suppression of mRNA translation under hypoxia is controlled through at least two distinct pathways; first by PERK-mediated phosphorylation of eIF2a which is required for the recruitment of aminoacylated tRNA, and second by disruption of the mRNA capbinding complex, eIF4F [28]. These changes can lead to altered sensitivity to chemotherapy and drive genetic instability
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