Epigenetic regulation of DNA repair genes and implications for tumor therapy.

DNA repair represents the first barrier against genotoxic stress causing metabolic changes, inflammation and cancer. Besides its role in preventing cancer, DNA repair needs also to be considered during cancer treatment with radiation and DNA damaging drugs as it impacts therapy outcome. The DNA repair capacity is mainly governed by the expression level of repair genes. Alterations in the expression of repair genes can occur due to mutations in their coding or promoter region, changes in the expression of transcription factors activating or repressing these genes, and/or epigenetic factors changing histone modifications and CpG promoter methylation or demethylation levels. In this review we provide an overview on the epigenetic regulation of DNA repair genes. We summarize the mechanisms underlying CpG methylation and demethylation, with de novo methyltransferases and DNA repair involved in gain and loss of CpG methylation, respectively. We discuss the role of components of the DNA damage response, p53, PARP-1 and GADD45a on the regulation of the DNA (cytosine-5)-methyltransferase DNMT1, the key enzyme responsible for gene silencing. We stress the relevance of epigenetic silencing of DNA repair genes for tumor formation and tumor therapy. A paradigmatic example is provided by the DNA repair protein O-methylguanine-DNA methyltransferase (MGMT), which is silenced in up to 40% of various cancers through CpG promoter methylation. The CpG methylation status of the MGMT promoter strongly correlates with clinical outcome and, therefore, is used as prognostic marker during glioblastoma therapy. Mismatch repair genes are also subject of epigenetic silencing, which was shown to correlate with colorectal cancer formation. For many other repair genes shown to be epigenetically regulated the clinical outcome is not yet clear. We also address the question of whether genotoxic stress itself can lead to epigenetic alterations of genes encoding proteins involved in the defense against genotoxic stress.