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
|
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: | Schools > Biosciences Schools > 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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