A Novel Role for DNA Mismatch Repair and the Autophagic Processing of Chemotherapy Drugs in Human Tumor Cells

Abstract

DNA Mismatch repair (MMR) maintains genome integrity by correcting DNA replication errors and blocking homologous recombination between divergent DNA sequences. The MMR system also activates both checkpoint and apoptotic responses following certain types of DNA damage. In a recent study, we describe a novel role for MMR in mediating an autophagic response to 6-thioguanine (6-TG), a DNA modifying chemical. Our results show that MMR proteins (MLH1 or MSH2) are required for signaling to the autophagic pathway after exposure to 6-TG. Using PFT-α, a p53 inhibitor, and shRNA-mediated silencing of p53 expression, we also show that p53 plays an essential role in the autophagic pathway downstream of the MMR system. This study suggests a novel function of MMR in mediating autophagy following chemical (6-TG) DNA mismatch damage through p53 activation. Here, we present the model and the clinical implications of the role of MMR in autophagy.Addendum to:DNA Mismatch Repair Initiates 6-Thioguanine-Induced Autophagy through p53 Activation in Human Tumor CellsX. Zeng, T. Yan, J.E. Schupp, Y. Seo and T.J. KinsellaClin Cancer Res 2007; 13:1315-21