Disrupting the function of the maintenance methyltransferase DNMT1 during Xenopus development leads to apoptosis and embryonic lethality, but what initiates apoptosis? Richard Meehan and colleagues now reveal that DNA mismatch repair (MMR) pathway components mediate this apoptotic induction (see ). First, the authors ruled out that DNMT1 methylase activity triggers the apoptosis. Instead, they show that overexpressing the methyl-CpG binding protein MBD4 or the MMR pathway protein MLH1 causes p53-dependent apoptosis, and that co-depleting either MBD4 or MLH1 rescues DNMT1-depleted embryos. They demonstrate that MBD4 interacts directly with DNMTs from various species. In mouse cells, MBD4 recruits MLH1 to methylated DNA sites that also contain DNMT1, and localised UV irradiation of nuclei triggers the recruitment of all three factors to sites of DNA damage. Based on these and other data, the authors suggest that chromatin-associated DNMT1, MBD4 and MLH1 can respond to DNA lesions either by repairing them or by triggering apoptosis through the release of an MBD4-MLH1 complex.
