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

Ruzov, Alexey, Shorning, Boris, Mortusewicz, Oliver, Dunican, Donncha S., Leonhardt, Heinrich and Meehan, Richard R. 2009. MBD4 and MLH1 are required for apoptotic induction in xDNMT1-depleted embryos. Development 136 (13) , pp. 2277-2286. 10.1242/dev.032227

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics
Uncontrolled Keywords:	DNMT1; MBD4; MLH1; Apoptosis; Xenopus
Publisher:	The Company of Biologists
ISSN:	0950-1991
Last Modified:	04 Jun 2017 05:05
URI:	https://orca.cardiff.ac.uk/id/eprint/48212

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