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DNA double-strand breaks (DSBs) occur in the cell either naturally through the stalling of replication forks, or artificially by an array of agents such as ionizing radiation and radiomimetic drugs. Despite their source, the accurate joining of DSBs by homologous recombination repair (HRR) is critical to the long term survival of the cell. The accumulation of breaks can lead to cell death by apoptosis, and inaccurate repair increases genomic instability, mutations and malignancy. MAPK family signaling regulates growth, survival and apoptosis. The MAPKs have also been shown to be central to the cellular response to ionizing radiation. The three major MAPK signaling pathways ERK, p38 and JNK have been shown to have both collaborative and antagonistic effects on these major cellular processes. To determine how MAPK signaling affects HRR, an I-SceI based repair assay was utilized in growth-arrested human glioma cells. The use of well-characterized inhibitors showed that ERK1/2 and JNK phosphorylation are important to HRR, blocking over 70% of HRR in both cases. In sharp contrast, inhibition of p38 MAPK stimulated HRR 1.4–1.7 fold. Interestingly, an increase in ERK1/2 phosphorylation was observed by western blotting when p38 MAPK was inhibited, suggesting the involvement of compensatory mechanisms. Further investigation of ERK1/2 involvement showed that when ERK1/2 signaling was stimulated by epidermal growth factor (EGF) a 2-fold increase in HRR was seen, which could be blocked by MEK1/2 inhibitors. These data suggest that EGF - MAPK signaling is involved in the regulation of HRR in human cells. It is clear that signaling through ERK1/2 and JNK is critical for efficient HRR and p38 MAPK signaling may exert a negative influence on ERK1/2 signaling and thus HRR. Supported by NIH CA72955.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]