PMID:14562041

Citation	Sansom, OJ, Zabkiewicz, J, Bishop, SM, Guy, J, Bird, A and Clarke, AR (2003) MBD4 deficiency reduces the apoptotic response to DNA-damaging agents in the murine small intestine. Oncogene 22:7130-6
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 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 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 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.
Links	PubMed Online version:10.1038/sj.onc.1206850
Keywords	Animals; Antineoplastic Agents/toxicity; Apoptosis/drug effects; Cell Survival/drug effects; Cell Survival/radiation effects; Cisplatin/toxicity; DNA Damage; DNA Repair/genetics; Dacarbazine/analogs & derivatives; Dacarbazine/toxicity; Endodeoxyribonucleases/deficiency; Endodeoxyribonucleases/genetics; Fluorouracil/toxicity; Intestinal Mucosa/drug effects; Intestinal Mucosa/pathology; Intestine, Small/cytology; Intestine, Small/drug effects; Intestine, Small/physiology; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout
edit table

Annotations

Gene product	Qualifier	GO ID	GO term name	Evidence Code	with/from	Aspect	Notes	Status
edit table

References

See Help:References for how to manage references in GONUTS.