Bellacosa A, Cicchillitti L, Schepis F, Riccio A, Yeung A T, Matsumoto Y, Golemis E A, Genuardi M, Neri G
Divisions of Population Science, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA.
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3969-74. doi: 10.1073/pnas.96.7.3969.
The DNA mismatch repair (MMR) is a specialized system, highly conserved throughout evolution, involved in the maintenance of genomic integrity. To identify novel human genes that may function in MMR, we employed the yeast interaction trap. Using the MMR protein MLH1 as bait, we cloned MED1. The MED1 protein forms a complex with MLH1, binds to methyl-CpG-containing DNA, has homology to bacterial DNA repair glycosylases/lyases, and displays endonuclease activity. Transfection of a MED1 mutant lacking the methyl-CpG-binding domain (MBD) is associated with microsatellite instability (MSI). These findings suggest that MED1 is a novel human DNA repair protein that may be involved in MMR and, as such, may be a candidate eukaryotic homologue of the bacterial MMR endonuclease, MutH. In addition, these results suggest that cytosine methylation may play a role in human DNA repair.
DNA错配修复（MMR）是一个在整个进化过程中高度保守的特殊系统，参与基因组完整性的维持。为了鉴定可能在MMR中发挥作用的新型人类基因，我们采用了酵母相互作用陷阱技术。以MMR蛋白MLH1作为诱饵，我们克隆出了MED1。MED1蛋白与MLH1形成复合物，结合含有甲基化CpG的DNA，与细菌DNA修复糖基化酶/裂解酶具有同源性，并表现出核酸内切酶活性。转染缺乏甲基化CpG结合结构域（MBD）的MED1突变体与微卫星不稳定性（MSI）相关。这些发现表明，MED1是一种新型的人类DNA修复蛋白，可能参与MMR，因此可能是细菌MMR核酸内切酶MutH的候选真核同源物。此外，这些结果表明胞嘧啶甲基化可能在人类DNA修复中发挥作用。
