MBD4 deficiency reduces the apoptotic response to DNA-damaging agents in the murine small intestine

Sansom, Owen J. ORCID: https://orcid.org/0000-0001-9540-3010, Zabkiewicz, Joanna ORCID: https://orcid.org/0000-0003-0951-3825, Bishop, Stefan Mark, Guy, Jackie, Bird, Adrian and Clarke, Alan Richard ORCID: https://orcid.org/0000-0002-4281-426X 2003. MBD4 deficiency reduces the apoptotic response to DNA-damaging agents in the murine small intestine. Oncogene 22 (46) , pp. 7130-7136. 10.1038/sj.onc.1206850

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Abstract

MBD4 was originally identified through its methyl binding domain, but has more recently been characterized as a thymine DNA glycosylase that interacts with the mismatch repair (MMR) protein MLH1. In vivo, MBD4 functions to reduce the mutability of methyl-CpG sites in the genome and mice deticient in MBD4 show increased intestinal tumorigenesis on an ApcMin/+ background. As MLH1 and other MMR proteins have been functionally linked to apoptosis, we asked whether MBD4 also plays a role in mediating the apoptotic response within the murine small intestine. Mice deficient for MBD4 showed significantly reduced apoptotic responses 6 h following treatment with a range of cytotoxic agents including -irradiation, cisplatin, temozolomide and 5-fluorouracil (5-FU). This leads to increased clonogenic survival in vivo in Mbd4-/- mice following exposure to either 5-FU or cisplatin. We next analysed the apoptotic response to 5-FU and temozolomide in doubly mutant Mbd4-/-, Mlh1-/- mice but observed no additive decrease. The results imply that MBD4 and MLH1 lie in the same pathway and therefore that MMR-dependent apoptosis is mediated through MBD4. MBD4 deficiency also reduced the normal apoptotic response to -irradiation, which we show is independent of Mlh1 status (at least in the murine small intestine), so suggesting that the reliance upon MBD4 may extend beyond MMR-mediated apoptosis. Our results establish a novel functional role for MBD4 in the cellular response to DNA damage and may have implications for its role in suppressing neoplasia.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine
Subjects:	Q Science > Q Science (General)
Uncontrolled Keywords:	MBD4; mismatch repair; apoptosis; DNA methylation; p53.
Publisher:	Nature Publishing
ISSN:	0950-9232
Last Modified:	25 Oct 2022 10:11
URI:	https://orca.cardiff.ac.uk/id/eprint/61363

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