MBD4 deficiency does not increase mutation or accelerate tumorigenesis in mice lacking MMR

Sansom, Owen J.; Bishop, Stefan Mark; Bird, Adrian; Clarke, Alan R.

doi:10.1038/sj.onc.1207767

Cited by 17 publications

(16 citation statements)

References 22 publications

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“…This observation indicates that the interaction between MBD4 and MMR may be important for the DNA damage signaling response. [84][85][86][87] Supporting this hypothesis, mice deficient for both MBD4 and MLH1 show no synergistic decrease in apoptosis when exposed to 5-fluorouracil or temozolamide, implying that MBD4 and MLH1 are involved in the same pathway and that MMRdependent apoptosis might be mediated through MBD4. The MMR/MBD4 interaction is not the only route by which MBD4 modulates the apoptotic response, as MBD4 has also been shown to have a functional interaction with the death domain protein FADD.…”

Section: Methyl-binding Domain Proteinmentioning

confidence: 69%

“…To test whether additional loss of MBD4 accelerated tumorigenesis on a MMR background, we also intercrossed MBD4 mice to mice mutant for either MLH1 or MSH2. 87 On both backgrounds, additional MBD4 deficiency did not alter tumorigenesis or mutation frequency at an endogenous locus, DLB1 (also known as DLEU1). The most likely interpretation of these data is that the MBD4 mutations seen in MMR-deficient tumors simply reflect the poly(A) tract repeat in human MBD4.…”

Section: Methyl-binding Domain Proteinmentioning

confidence: 98%

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Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer

2007

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The methyl-CpG-binding domain (MBD) proteins 'read' and interpret the methylation moieties on DNA, and thus are critical mediators of many epigenetic processes. Currently, the MBD family comprises five members; MBD1, MBD2, MBD3, MBD4 and MeCP2. Although not a 'classical' MBD protein, Kaiso also mediates transcriptional repression by using zinc finger domains to bind its targets. Since DNA hypermethylation is a well-recognized mechanism underlying gene silencing events in both tumorigenesis and drug resistance, it is likely that the MBD proteins may be important modulators of tumorigenesis. We review the recent work addressing this possibility, and discuss several of the MBD proteins as potentially excellent novel therapeutic targets.

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Section: Methyl-binding Domain Proteinmentioning

confidence: 69%

Section: Methyl-binding Domain Proteinmentioning

confidence: 98%

Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer

2007

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“…The tumorigenic effect may be due to an increase in MF, decreased apoptosis or a combination of both. However, absence of Mbd4 in an MSH2-null background does not increase tumorigenicity above that seen owing to the MMR-deficiency (Sansom et al, 2004).…”

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confidence: 88%

A human cancer-associated truncation of MBD4 causes dominant negative impairment of DNA repair in colon cancer cells

2007

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MBD4 binds to methylated DNA and acts as a thymine DNA glycosylase in base excision repair. Deficiency of MBD4 in mice enhances mutation at CpG sites and alters apoptosis in response to DNA damage, but does not increase tumorigenesis in mismatch repair-deficient mice. However, in humans, frameshift mutation of MBD4, rather than deletion, is what occurs in up to 43% of microsatellite unstable colon cancers. There is no murine equivalent of this mutation. We now show that recombinant truncated MBD4 (MBD4 tru ) inhibits glycosylase activities of normal MBD4 or Uracil DNA glycosylase in cell-free assays as a dominant negative effect. Furthermore, overexpression of MBD4 tru in Big Blue (lacI)-transfected, MSI human colorectal carcinoma cells doubled mutation frequency, indicating that the modest dominant negative effect on DNA repair can occur in living cells in short-term experiments. Intriguingly, the whole mutation spectrum was increased, not only at CpG sites, suggesting that truncated MBD4 has a more widespread effect on genomic stability. This demonstration of a dominant negative effect may be of significance in tumour progression and acquisition of drug resistance.

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“…However, there are controversial reports about its function in tumorigenesis; MBD4 mutations are generally monoallelic, predominantly at the poly(A) tract, and have not been detected in DNA mismatch repairproficient tumors. Moreover, a recent study demonstrated that loss of MBD4 does not alter the spontaneous mutation rate, the tumor onset, or the tumor spectrum in mismatch repairdeficient mice (29). Therefore, there is the possibility that MBD4 mutations by themselves may simply reflect microsatellite instability in mismatch repair-deficient tumors and may have no relationship with cancer development in these tumors.…”

Section: Methyl-cpg (Mcpg) Binding Domain Protein 4 (Mbd4)mentioning

confidence: 99%

The Thymine DNA Glycosylase MBD4 Represses Transcription and Is Associated with Methylated p16^INK4a and hMLH1 Genes

Kondo

Horii

et al. 2005

Molecular and Cellular Biology

100

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Epigenetic silencing through methyl-CpG (mCpG) is implicated in many biological patterns such as genome imprinting, X chromosome inactivation, and cancer development. In this process, the mCpG binding domain (MBD) proteins play an essential role in transmitting epigenetic information to downstream regulatory proteins. Among the five MBD proteins identified so far, MBD4 has been the only exception; it has long been thought to be a DNA repair protein. Herein we demonstrate that MBD4 has the ability to repress transcription through mCpG. Transcriptional repression by the MBD4 is histone deacetylase (HDAC) dependent, and MBD4 directly binds to Sin3A and HDAC1 at three central regions that overlap transcriptional repression domains. Furthermore, a chromatin immunoprecipitation assay clearly shows that MBD4 binds to hypermethylated promoters of the p16INK4a and hMLH1 genes. These results suggest that MBD4 is one of the essential components involved in epigenetic silencing in cancer and its repair activity is necessary for the maintenance of hypermethylated promoters.

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MBD4 deficiency does not increase mutation or accelerate tumorigenesis in mice lacking MMR

Cited by 17 publications

References 22 publications

Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer

Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer

A human cancer-associated truncation of MBD4 causes dominant negative impairment of DNA repair in colon cancer cells

The Thymine DNA Glycosylase MBD4 Represses Transcription and Is Associated with Methylated p16^INK4a and hMLH1 Genes

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MBD4 deficiency does not increase mutation or accelerate tumorigenesis in mice lacking MMR

Cited by 17 publications

References 22 publications

Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer

Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer

A human cancer-associated truncation of MBD4 causes dominant negative impairment of DNA repair in colon cancer cells

The Thymine DNA Glycosylase MBD4 Represses Transcription and Is Associated with Methylated p16INK4a and hMLH1 Genes

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The Thymine DNA Glycosylase MBD4 Represses Transcription and Is Associated with Methylated p16^INK4a and hMLH1 Genes