Zeng Xuehuo, Kinsella Timothy J
Department of Radiation Oncology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, Ohio 44106-6068, USA.
Autophagy. 2007 Jul-Aug;3(4):368-70. doi: 10.4161/auto.4205. Epub 2007 Jul 29.
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-alpha, 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.
DNA错配修复（MMR）通过纠正DNA复制错误和阻止不同DNA序列之间的同源重组来维持基因组完整性。MMR系统还会在某些类型的DNA损伤后激活检查点和凋亡反应。在最近的一项研究中，我们描述了MMR在介导对6-硫鸟嘌呤（6-TG，一种DNA修饰化学物质）的自噬反应中的新作用。我们的结果表明，暴露于6-TG后，MMR蛋白（MLH1或MSH2）是向自噬途径发出信号所必需的。使用p53抑制剂PFT-α以及shRNA介导的p53表达沉默，我们还表明p53在MMR系统下游的自噬途径中起重要作用。这项研究表明，MMR通过激活p53在化学（6-TG）DNA错配损伤后介导自噬具有新功能。在此，我们展示了MMR在自噬中的作用模型及其临床意义。
