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First published online June 5, 2009
doi: 10.1242/10.1242/dev.032227

Development 136, 2277-2286 (2009)
Published by The Company of Biologists 2009
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MBD4 and MLH1 are required for apoptotic induction in xDNMT1-depleted embryos

Alexey Ruzov1,*, Boris Shorning2,*,{dagger}, Oliver Mortusewicz3,*, Donncha S. Dunican1, Heinrich Leonhardt3 and Richard R. Meehan1,2,4,{ddagger}

1 Human Genetics Unit, MRC, IGMM, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
2 Genes and Development Group, School of Biomedical and Clinical Laboratory Sciences, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
3 Ludwig Maximilians University Munich, Department of Biology II and Center for Integrated Protein Science (CiPS), 82152 Planegg-Martinsried, Germany.
4 Edinburgh Breakthrough Breast Cancer Research Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.

{ddagger} Author for correspondence (e-mail: Richard.Meehan{at}hgu.mrc.ac.uk)

Accepted 28 April 2009

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.

Key words: DNMT1, MBD4, MLH1, Apoptosis, Xenopus


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