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

Sansom, O. , Zabkiewicz, J., Bishop, S., Guy, J., Bird, A. and Clarke, A. (2003) MBD4 deficiency reduces the apoptotic response to DNA-damaging agents in the murine small intestine. Oncogene, 22(46), pp. 7130-7136. (doi: 10.1038/sj.onc.1206850)

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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 Apc(Min/)+ 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 gamma-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 5FU 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 gamma-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:Articles
Glasgow Author(s) Enlighten ID:Sansom, Professor Owen
Authors: Sansom, O., Zabkiewicz, J., Bishop, S., Guy, J., Bird, A., and Clarke, A.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Oncogene

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