MED1: A central molecule for maintenance of genome integrity and response to DNA damage
- Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, United States Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079
Maintaining genome integrity is a dynamic process that involves many different cellular pathways, including methylation maintenance, homologous recombination, DNA replication, DNA repair, and cell cycle control. A defect in one or more of these pathways can compromise genome integrity and result in cancer. A number of DNA repair proteins have been identified that also impact the regulation of the cell cycle and/or apoptosis (1, 2). Individuals carrying germ-line mutations in such genes, like MLH1 or BRCA1, are predisposed to develop cancer (2). In this issue of PNAS, Cortellino et al. (3) provide evidence that MED1 belongs to this critical group of multifunction proteins. They show that MED1 impacts three processes necessary for the maintenance of genome integrity: base excision repair (BER), DNA mismatch repair (MMR), and the cell cycle response to DNA damage. Their work adds significant information to the growing body of research on the function of MED1 in maintenance of genome integrity (Fig. 1).
Summary of known MED1 functions and the cellular processes impacted by MED1 functions.
The multifunctional nature of MED1, also known as MBD4, was apparent from the time of the molecule's discovery. The molecule was identified by using two different screening methods. The human and mouse MBD4 genes were isolated based on DNA sequence homology to the methyl-binding domain of MeCP2, a human 5-methylcytosine (5-meC) binding protein and transcriptional repressor (4). It was shown that the MBD4 gene product could bind 5-meC both in vitro and in vivo. Thus, the first functional description …
