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Development July 1, 2009; 136 (13): 2277-86.

MBD4 and MLH1 are required for apoptotic induction in xDNMT1-depleted embryos.

Ruzov A , Shorning B , Mortusewicz O , Dunican DS , Leonhardt H , Meehan RR .

Loss of the of the maintenance methyltransferase xDNMT1 during Xenopus development results in premature transcription and activation of a p53-dependent apoptotic program that accounts for embryo lethality. Here, we show that activation of the apoptotic response is signalled through the methyl-CpG binding protein xMBD4 and the mismatch repair pathway protein xMLH1. Depletion of xMBD4 or xMLH1 increases the survival rate of xDNMT1-depleted embryos, whereas overexpression of these proteins in embryos induces programmed cell death at the onset of gastrulation. MBD4 interacts directly with both DNMT1 and MLH1, leading to recruitment of the latter to heterochromatic sites that are coincident with DNMT1 localisation. Time-lapse microscopy of micro-irradiated mammalian cells shows that MLH1/MBD4 (like DNMT1) can accumulate at DNA damage sites. We propose that xMBD4/xMLH1 participates in a novel G2 checkpoint that is responsive to xDNMT1p levels in developing embryos and cells.

PubMed ID: 19502488
PMC ID: PMC2729342
Article link: Development
Grant support: [+]
Genes referenced: dnmt1 mbd4 mlh1 tp53 zbtb33

References [+] :
Agoston, Increased protein stability causes DNA methyltransferase 1 dysregulation in breast cancer. 2005, Pubmed

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