Mbd4 inactivation increases C→T transition mutations and promotes gastrointestinal tumor formation

Wong, Edmund; Yang, Kan; Kuraguchi, Mari; Werling, Uwe; Avdievich, Elena; Fan, Kunhua; Fazzari, Melissa; Jin, Bo; Brown, Anthony M.; Lipkin, Martin; Edelmann, Winfried

doi:10.1073/pnas.232579299

Cited by 157 publications

(160 citation statements)

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“…Some other base-pair mismatches affecting CpG dinucleotides were also shown to be lower affinity substrates for MBD4 activity (Petronzelli et al, 2000a, b) and as time has progressed more substrates have been documented, at least in vitro (Liu et al, 2002;Yoon et al, 2003). The role of MBD4 as a methyl-CpG-focused DNA mismatch glycosylase was subsequently supported by increases in mutation frequency at CpG sites in mouse models lacking Mbd4 (Millar et al, 2002;Wong et al, 2002). However, we and others have found an association of truncating mutations of MBD4 in human MSI cancers, especially colon, and in most cases these mutations occur in the presence of a remaining intact MBD4 allele (Bader et al, 1999(Bader et al, , 2000Riccio et al, 1999), that is, the null genotype is not seen naturally.…”

Section: Discussionmentioning

confidence: 99%

“…Later reports demonstrated a larger set of in vitro CpG mismatches for MBD4 recognition, such as U Á G (Petronzelli et al, 2000a, b), 5-fluorouracil (5-FU) Á G (Petronzelli et al, 2000b), ethenecytosine (eC) Á G (Petronzelli et al, 2000a), 5-formyluracil (5-FoU) Á G (Liu et al, 2002), T Á O 6 -methyl-guanine (O 6 -meG) (Cortellino et al, 2003) and thymine glycol (Tg) Á G (Yoon et al, 2003). Total absence of MBD4 in mice caused an increase in MF especially at CpG sites (Millar et al, 2002;Wong et al, 2002). This was as predicted from the originally reported range of substrates and by the fact that the other main T Á G mismatch enzyme, Thymine DNA glycosylase (TDG), does not have an MBD and so does not focus on methyl-CpG sites.…”

Section: Discussionmentioning

confidence: 99%

“…MBD4 has been shown in vitro to excise mismatched thymine (T) bases from oligo templates Petronzelli et al, 2000a, b), and mouse knockout models have found that in the absence of Mbd4, mutation frequency (MF) in vivo increases, mainly at methyl-CpG sites (Millar et al, 2002;Wong et al, 2002). MBD4 can also bind to MLH1 and Fas-associated death domain (FADD) proteins Screaton et al, 2003), and the small intestine of Mbd4 À/À mice shows reduced apoptosis in response to a variety of DNA-damaging agents (Cortellino et al, 2003;Sansom et al, 2003;Screaton et al, 2003).…”

mentioning

confidence: 99%

“…MBD4 can also bind to MLH1 and Fas-associated death domain (FADD) proteins Screaton et al, 2003), and the small intestine of Mbd4 À/À mice shows reduced apoptosis in response to a variety of DNA-damaging agents (Cortellino et al, 2003;Sansom et al, 2003;Screaton et al, 2003). Absence of Mbd4 in mice also increases tumorigenicity in the tumour-susceptible APC min background (Millar et al, 2002;Wong et al, 2002). The tumorigenic effect may be due to an increase in MF, decreased apoptosis or a combination of both.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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

2007

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“…Tail DNA from six WT, six Pms2 +/EK , six Pms2 EK/EK , and six Pms2 −/− mice was pooled and diluted to approximately one molecule per reaction. The microsatellite loci were amplified and analyzed as described previously (36).…”

Section: Methodsmentioning

confidence: 99%

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance

Oers

Roa

Werling

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The DNA mismatch repair protein PMS2 was recently found to encode a novel endonuclease activity. To determine the biological functions of this activity in mammals, we generated endonuclease-deficient Pms2 E702K knock-in mice. Pms2 EK/EK mice displayed increased genomic mutation rates and a strong cancer predisposition. In addition, class switch recombination, but not somatic hypermutation, was impaired in Pms2 EK/EK B cells, indicating a specific role in Ig diversity. In contrast to Pms2 −/− mice, Pms2 EK/EK male mice were fertile, indicating that this activity is dispensable in spermatogenesis. Therefore, the PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance and tumor suppression.DNA mismatch repair | B cell lymphoma | class switch recombination | somatic hypermutation | spermatogenesis P MS2 is an essential component of DNA mismatch repair (MMR) complexes, which play an important role in maintaining genetic stability. MMR functions primarily in the detection and repair of mismatched bases that result from erroneous replication, and also plays important roles in DNA damage response, genetic recombination, control of meiotic progression, and generation of antibody diversity (1). During MMR, heterodimeric MutS homolog (MSH) complexes, consisting of either MSH2 and MSH6 (MutSα) or MSH2 and MSH3 (MutSβ), bind to mismatched bases. On binding, a conformational change in the MutS complexes activates downstream events and leads to the recruitment of MutL homolog (MLH) complexes consisting of either MLH1 and PMS2 (MutLα) or MLH1 and MLH3 (MutLγ). MutLα interacts with the MutS complexes via MLH1, and this interaction is essential for the coordination of downstream repair events, including excision of the mismatch carrying strand and its resynthesis (2, 3).Important insights into the role of MutLα in MMR came from biochemical studies of reconstituted human MMR (4, 5), which showed that PMS2 is a latent endonuclease that introduces additional nicks into the discontinuous DNA strand of nicked heteroduplex substrates. This activity is dependent on the integrity of a highly conserved metal-binding motif found in many MutL homologs, including MLH3. MutLα appears to play an essential role in 3′-directed MMR, where the bias for incision on the distal side of the mismatch results in a 5′ entry site for MutSα-activated Exo1. For 5′-directed MMR, however, several studies in both the reconstituted human MMR system and MutLα-deficient cells have shown that MutLα is not essential, and that a purified system consisting of MutSα, Exo1, and RPA is sufficient to support 5′-directed MMR (6, 7). Studies in yeast have further delineated roles of the PMS2 endonuclease activity in DNA repair, recombination, and the DNA damage response (5,8,9).Pms2 −/− mice (10) showed an increase in base substitution and insertion/deletion mutation frequencies at both a reporter locus and microsatellite sequences, with a higher proportion of frameshift mutations compared with other MMR knockout models, such as...

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MBD4/MED1 Protein in DNA Repair and Demethylation, Cancer, and Other Diseases

2011

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Mbd4 inactivation increases C→T transition mutations and promotes gastrointestinal tumor formation

Abstract: Mbd4 (methyl-CpG

Cited by 157 publications

References 33 publications

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

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

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance

MBD4/MED1 Protein in DNA Repair and Demethylation, Cancer, and Other Diseases

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