Hypoxia Provokes Base Excision Repair Changes and a Repair-deficient, Mutator Phenotype in Colorectal Cancer Cells.

Molecular cancer research : MCR

PubMedID: 25030372

Chan N, Ali M, McCallum GP, Kumareswaran R, Koritzinsky M, Wouters BG, Wells PG, Gallinger S, Bristow RG. Hypoxia Provokes Base Excision Repair Changes and a Repair-deficient, Mutator Phenotype in Colorectal Cancer Cells. Mol Cancer Res. 2014;.
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 (DDR) 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 regarding the expression and function of BER proteins under hypoxic stress. Using conditions of chronic hypoxia, decreased expression of BER proteins was observed due to 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 h after H2O2 treatment as compared to normoxic controls. Similarly, HPLC analysis demonstrated that 8-oxo-2'-deoxyguanosine (8-OHdG) lesions were elevated in hypoxic cells 3 and 24 h after potassium bromate (KBrO3) treatment when compared to 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 down-regulation of BER components by the microenvironment modifies and facilitates a mutator phenotype, driving genetic instability and cancer progression. Implications: Aberrant BER is a contributing factor for the observed genetic instability in hypoxic tumor cells.