MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1

Bellacosa, Alfonso; Cicchillitti, Lucia; Schepis, Filippo; Riccio, Antonio; Yeung, Anthony T.; Matsumoto, Yoshihiro; Golemis, Erica A.; Genuardi, Maurizio; Neri, Giovanni

doi:10.1073/pnas.96.7.3969

Cited by 230 publications

(197 citation statements)

References 34 publications

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“…The BER enzyme SMUG1 removes FdU from DNA and confers protection from cell killing . MED1 (MBD4), a BER N-glycosylase also targets halogenated pyrimidines, and by analogy to MMR, loss of MED1 confers resistance to FdU (Bellacosa et al, 1999). Interestingly, MED1 was isolated in a two-hybrid screen using MLH1 as bait (Cortellino et al, 2003).…”

Section: Mmr and Dna Damage Signallingmentioning

confidence: 99%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

397

359

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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Section: Mmr and Dna Damage Signallingmentioning

confidence: 99%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

397

359

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“…MLH1 forms heterodimers with other MutL homologues, PMS2, PMS1 and MLH3, through a conserved putative coiled coil domain in the MutL partners (Kondo et al, 2001). MLH1 can also interact with MBD4 (MED1), a methyl-CpG-binding domain protein (Bellacosa et al, 1999). Interactions between MLH1 and the replication factor PCNA (proliferating cell nuclear antigen) have also been demonstrated, leading to the suggestion that MutL heterodimers act to interface MutS heterodimers bound to DNA mismatches and DNA replication components (Umar et al, 1996;Bowers et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…These screens identified genes encoding proteins known to interact with MLH1, such as PMS1, MLH3 and MED1/MBD4 (Bellacosa et al, 1999;Raschle et al, 1999;Kondo et al, 2001). A yeast two-hybrid screen of normal human Mammary Gland Matchmaker cDNA library (Clontech) identified the carboxy terminus of the human c-MYC proto-oncogene as an interacting sequence.…”

Section: Yeast Two-hybrid Analysis Of Interactions Between Mlh1 and Cmentioning

confidence: 99%

Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX

et al. 2003

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MSH2 and MLH1 have a central role in correcting mismatches in DNA occurring during DNA replication and have been implicated in the engagement of apoptosis induced by a number of cytotoxic anticancer agents. The function of MLH1 is not clearly defined, although it is required for mismatch repair (MMR) and engagement of apoptosis after certain types of DNA damage. In order to identify other partners of MLH1 that may be involved in signalling MMR or apoptosis, we used human MLH1 in yeast two-hybrid screens of normal human breast and ovarian cDNA libraries. As well as known partners of MLH1 such as PMS1, MLH3 and MBD4, we identified the carboxy terminus of the human c-MYC protooncogene as an interacting sequence. We demonstrate, both in vitro by yeast two-hybrid and GST-fusion pulldown experiments, as well as in vivo by coimmunoprecipitation from human tumour cell extracts, that MLH1 interacts with the c-MYC protein. We further demonstrate that the heterodimeric partner of c-MYC, MAX, interacts with a different MMR protein, MSH2, both in vitro and in vivo. Using an inducible c-MYC-ERt fusion gene, we show that elevated c-MYC expression leads to an increased HGPRT mutation rate of Rat1 cells and an increase in the number of frameshift mutants at the HGPRT locus. The effect on HGPRT mutation rate is small (2-3-fold), but is consistent with deregulated c-MYC expression partially inhibiting MMR activity.

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“…The MBD4 gene maps to chromosome 3q21-22, 35 and the MBD4 protein interacts with MLH1, alteration of which is known to result in HNPCC. 36 Importantly, the MBD4 gene contains one polyA (10) and three polyA (6) repeat tracts in exon 3 within the coding region of the gene. 37,38 Tumors resulting from alteration of mismatch repair genes and with high levels of microsatellite instability (MSI-H) synthesize a truncated MBD4 protein due to mutation of these repeats, as shown in Table 1.…”

mentioning

confidence: 99%

Is Base Excision Repair a Tumor Suppressor Mechanism?

Sweasy¹,

Lang²,

DiMaio³

2006

Cell Cycle

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The base excision repair pathway is critical for the removal of oxidized and methylated bases from the DNA. Much of this DNA damage arises endogenously, as a result of oxygen metabolism. Several proteins including DNA glycosylases, the APE1 endonuclease, DNA polymerase β and DNA ligase, act in a highly regulated and coordinated manner during base excision repair to excise the base adducts from the DNA and restore the normal DNA sequence. Both germline and tumor-associated variants of genes encoding these proteins have been identified in humans. In many cases, the protein variant has been shown to have properties that could contribute to the development of cancer, suggesting that base excision repair acts as a tumor suppressor mechanism in humans. Limited epidemiological studies are consistent with this view. Our review of the literature indicates that additional laboratory and epidemiological studies of the role of base excision repair in cancer etiology is warranted.

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MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1

Cited by 230 publications

References 34 publications

DNA mismatch repair: Molecular mechanism, cancer, and ageing

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX

Is Base Excision Repair a Tumor Suppressor Mechanism?

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