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Mbd4  -  methyl-CpG binding domain protein 4

Mus musculus

Synonyms: Med1, Methyl-CpG-binding domain protein 4, Methyl-CpG-binding protein MBD4, Mismatch-specific DNA N-glycosylase
 
 
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High impact information on Mbd4

  • Within the nucleus, FADD interacted with the methyl-CpG binding domain protein 4 (MBD4), which excises thymine from GT mismatches in methylated regions of chromatin [1].
  • Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: a potential link between genome surveillance and apoptosis [1].
  • Although Mbd4 inactivation did not increase microsatellite instability (MSI) in the mouse genome, it did result in a 2- to 3-fold increase in C-->T transition mutations at CpG sequences in splenocytes and epithelial cells of the small intestinal mucosa [2].
  • To clarify the role of Mbd4 in DNA repair in vivo and to examine the impact of Mbd4 inactivation on gastrointestinal (GI) tumorigenesis, we introduced a null mutation into the murine Mbd4 gene by gene targeting [2].
  • These studies indicate that, although inactivation of Mbd4 does not by itself cause cancer predisposition in mice, it can alter the mutation spectrum in cancer cells and modify the cancer predisposition phenotype [2].
 

Biological context of Mbd4

  • Mbd4 (methyl-binding domain 4) has been shown to be mutated in a high percentage of mismatch repair (MMR)-deficient colorectal tumours that exhibit microsatellite instability (MSI) [3].
 

Anatomical context of Mbd4

  • In addition, the hypermutated JH2 to JH4 region in Peyer's patch B cells showed no effects as a result of Mbd4 deficiency [4].
 

Associations of Mbd4 with chemical compounds

  • We tested this hypothesis by analyzing Mbd4-/- mice and found that the frequency of of C --> T transitions at CpG sites was increased by a factor of three [5].
  • We next analysed the apoptotic response to 5-FU and temozolomide in doubly mutant Mbd4(-/-), Mlh1(-/-) mice but observed no additive decrease [6].
  • This leads to increased clonogenic survival in vivo in Mbd4(-/-) mice following exposure to either 5-FU or cisplatin [6].
  • Mismatch repair in methylated DNA. Structure and activity of the mismatch-specific thymine glycosylase domain of methyl-CpG-binding protein MBD4 [7].
 

Other interactions of Mbd4

  • On a cancer-susceptible Apc(Min/+) background, Mbd4-/- mice showed accelerated tumor formation with CpG --> TpG mutations in the Apc gene [5].
  • To determine whether Mbd4 functions downstream of activation-induced cytidine deaminase activity, we examined somatic hypermutation and CSR in Mbd4(-/-) mice [4].
 

Analytical, diagnostic and therapeutic context of Mbd4

  • In this study, we report that CSR, as analyzed by an in vitro switch assay and by in vivo immunizations, is unaffected in Mbd4(-/-) mice [4].

References

  1. Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: a potential link between genome surveillance and apoptosis. Screaton, R.A., Kiessling, S., Sansom, O.J., Millar, C.B., Maddison, K., Bird, A., Clarke, A.R., Frisch, S.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  2. Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation. Wong, E., Yang, K., Kuraguchi, M., Werling, U., Avdievich, E., Fan, K., Fazzari, M., Jin, B., Brown, A.M., Lipkin, M., Edelmann, W. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  3. MBD4 deficiency does not increase mutation or accelerate tumorigenesis in mice lacking MMR. Sansom, O.J., Bishop, S.M., Bird, A., Clarke, A.R. Oncogene (2004) [Pubmed]
  4. Cutting edge: the G-U mismatch glycosylase methyl-CpG binding domain 4 is dispensable for somatic hypermutation and class switch recombination. Bardwell, P.D., Martin, A., Wong, E., Li, Z., Edelmann, W., Scharff, M.D. J. Immunol. (2003) [Pubmed]
  5. Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Millar, C.B., Guy, J., Sansom, O.J., Selfridge, J., MacDougall, E., Hendrich, B., Keightley, P.D., Bishop, S.M., Clarke, A.R., Bird, A. Science (2002) [Pubmed]
  6. MBD4 deficiency reduces the apoptotic response to DNA-damaging agents in the murine small intestine. Sansom, O.J., Zabkiewicz, J., Bishop, S.M., Guy, J., Bird, A., Clarke, A.R. Oncogene (2003) [Pubmed]
  7. Mismatch repair in methylated DNA. Structure and activity of the mismatch-specific thymine glycosylase domain of methyl-CpG-binding protein MBD4. Wu, P., Qiu, C., Sohail, A., Zhang, X., Bhagwat, A.S., Cheng, X. J. Biol. Chem. (2003) [Pubmed]
 
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