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 γ-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 γ-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.
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References
Bader S, Walker M and Harrison D . (2000). Br. J. Cancer, 83, 1646–1649.
Bader S, Walker M, Heindrich B, Bird A, Bird C, Hooper M and Wyllie A . (1999). Oncogene, 18, 8044–8047.
Bellacosa A . (2001). J. Cell. Physiol., 187, 137–144.
Bellacosa A, Cicchillitti L, Schepis F, Riccio A, Yeung AT, Matsumoto Y, Golemis EA, Genuardi M and Neri G . (1999). Proc. Natl. Acad. Sci. USA, 96, 3969–3975.
Buermeyer AB, Deschennes SM, Baker SM and Liskay RM . (1999). Annu. Rev. Genet., 33, 533–564.
Drummond JT and Bellacosa A . (2001). Nucleic Acid Res., 29, 2234–2243.
Fishel R . (1999). Nat. Med., 5, 1239–1241.
Hendrich B and Bird A . (1998). Mol. Cell. Biol., 18, 6538–6547.
Hendrich B, Hardeland U, Ng HH, Jiricny J and Bird A . (1999). Nature, 401, 301–304.
Hendry JH, Cai WB, Roberts SA and Potten CS . (1997). Radiat. Res., 148, 254–259.
Herr I, Wilhelm D, Bohler T, Angel P and Debatin K-M . (1997). EMBO J., 16, 6200–6208.
Ijiri K and Potten CS . (1983). Br. J. Cancer, 47, 175–185.
Karran P and Bignami M . (1992). Nucleic Acid Res., 20, 2933–2940.
Meyers M, Wagner MW, Hwang HS, Kinsella TJ and Boothman DA . (2001). Cancer Res., 61, 5193–5201.
Micheau O, Solary E, Hammann A and Dimanche-Boitrel MT . (1999). J. Biol. Chem., 274, 7987–7992.
Millar CB, Guy J, Sansom OJ, Selfridge J, MacDougall E, Hendrich B, Keightley PD, Bishop SM, Clarke AR and Bird A . (2002). Science, 297, 403–405.
Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D, Haimovitz-Friedman A, Cordon-Cardo C and Kolesnick R . (2001). Science, 293, 293–297.
Petronzelli F, Riccio A, Markham GD, Seeholzer SH, Genuardi M, Karbowski M, Yeung AT, Matsumoto Y and Bellacosa A . (2000). J. Biol. Chem., 185, 473–480.
Potten CS . (1990). Int. J. Radiat. Biol., 58, 925–973.
Pritchard DM, Potten CS and Hickman JA . (1998). Cancer Res., 58, 5453–5465.
Prolla TA, Baker SM, Harris AC, Tsao EL, Yao X, Bronner CE, Zheng BH, Gordon M, Reneker J, Amheim N, Shibata D, Bradley A and Liskay RM . (1998). Nat. Genet., 18, 276–279.
Riccio A, Aaltonen LA, Godwin AK, Loukola A, Percesepe A, Salovaara R, Masciullo V, Genuardi M, Paravatou-Petsotas M, Bassi DE, Ruggeri BA, Klein-Szanto AJP, Testa JR, Neri G and Bellacosa A . (1999). Nat. Genet., 23, 266–268.
Sansom OJ and Clarke AR . (2000). Mutation Res.-Fundam. Mol. Mech. Mutagen., 452, 149–162.
Sansom OJ and Clarke AR . (2002). Oncogene, 21, 5934–5399.
Sansom OJ, Toft NJ, Winton DJ and Clarke AR . (2001). Oncogene, 20, 3580–3584.
Screaton RA, Kiessling S, Sansom OJ, Millar CB, Maddison K, Bird A, Clarke AR, Frisch SM . (2003). Proc. Natl. Acad. USA, 100, 5211–5216.
Toft NJ, Winton DJ, Kelly J, Howard LA, Dekker M, Riele HT, Arends MJ, Wyllie AH, Margison GP and Clarke AR . (1999). Proc. Natl. Acad. USA, 96, 3911–3915.
Acknowledgements
We thank Nathan Hill for maintenance of animal stocks and Steven Frisch for helpful discussions. This work was supported by Grants from the Cancer Research UK and the Wellcome trust.
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Sansom, O., Zabkiewicz, J., Bishop, S. et al. MBD4 deficiency reduces the apoptotic response to DNA-damaging agents in the murine small intestine. Oncogene 22, 7130–7136 (2003). https://doi.org/10.1038/sj.onc.1206850
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DOI: https://doi.org/10.1038/sj.onc.1206850
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