Insight into the functional consequences of hMYH variants associated with colorectal cancer: distinct differences in the adenine glycosylase activity and the response to AP endonucleases of Y150C and G365D murine MYH

Pope, Mary Ann; Chmiel, Nikolas H.; David, Sheila S.

doi:10.1016/j.dnarep.2004.10.003

Cited by 54 publications

(70 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The major exception is MUTYH where individuals with biallalic mutations in this gene are predisposed to the familial adenomatous polyposis coli (APC) form of colon cancer with G-T mutations in the APC gene. 93,[224][225][226] Recent studies have focused on potential correlations between human polymorphic variants of BER proteins and cancer predisposition (for reviews see refs. [227][228][229].…”

Section: Dna Glycosylase Biologymentioning

confidence: 99%

Consequences and Repair of Oxidative DNA Damage

Duclos¹,

Doublié²,

Wallace³

2012

Issues in Toxicology

View full text Add to dashboard Cite

Section: Dna Glycosylase Biologymentioning

confidence: 99%

Consequences and Repair of Oxidative DNA Damage

Duclos¹,

Doublié²,

Wallace³

2012

Issues in Toxicology

View full text Add to dashboard Cite

“…Over 50 different missense and in-frame deletion mutations in MUTYH have been observed in colorectal cancer patients. Many of these single site mutants have been evaluated for their effect on MutY enzyme activity, but it is clear that defects in the rate of excision and substrate binding affinity may not account for all of the deficiencies observed with these mutants in vivo [48,49]. An increasing body of evidence indicates that finding the lesion is likely the limiting step in effective BER inside the cell [50] and it is, therefore, of critical importance to understand all of the strategies employed by these proteins to detect damage.…”

Section: The Possibility Of Dna-mediated Signaling Among Proteinsmentioning

confidence: 99%

Biological contexts for DNA charge transport chemistry

Merino

Boal

Barton

2008

Current Opinion in Chemical Biology

114

105

View full text Add to dashboard Cite

SUMMARYMany experiments have now shown that double helical DNA can serve as a conduit for efficient charge transport (CT) reactions over long distances in vitro. These results prompt the consideration of biological roles for DNA-mediated CT. DNA CT has been demonstrated to occur in biologically relevant environments such as within the mitochondria and nuclei of HeLa cells as well as in isolated nucleosomes. In mitochondria, DNA damage that results from CT is funneled to a critical regulatory element. Thus DNA CT provides a strategy to funnel damage to particular sites in the genome. DNA CT might also be important in long range signaling to DNA-bound proteins. Both DNA repair proteins, containing Fe-S clusters, and the transcription factor, p53, which is regulated through thiol-disulfide switches, can be oxidized from a distance through DNA-mediated CT. These observations highlight a means through which oxidative stress may be chemically signaled in the genome over long distances through CT from guanine radicals to DNAbound proteins. Moreover, DNA-mediated CT may also play a role in signaling among DNAbinding proteins, as has been proposed as a mechanism for how DNA repair glycosylases more efficiently detect lesions inside the cell.

show abstract

“…10,24 The two most common missense amino acid substitutions in MUTYH result in reduced glycosylase activity and affinity for OG-containing substrates. 40 In addition, the corresponding E. coli variants are unable to distinguish OG from G. 25,36 This suggests that the function of MutY and its human homologue to prevent deleterious DNA mutations is critically dependent on the ability to detect OG and select the appropriate undamaged A for excision to initiate BER. …”

mentioning

confidence: 99%

Unnatural substrates reveal the importance of 8-oxoguanine for in vivo mismatch repair by MutY

et al. 2007

View full text Add to dashboard Cite

Escherchia coli MutY plays an important role in preventing mutations associated with the oxidative lesion 7,8-dihydro-8-oxo-2′-deoxyguanosine (OG) in DNA by excising adenines from OG:A mismatches as the first step of base excision repair. To determine the importance of specific steps in the base pair recognition and base removal process of MutY, we have evaluated the effects of modifications of the OG:A substrate on the kinetics of base removal, mismatch affinity and repair to G:C in an Escherchia coli-based assay. Surprisingly, adenine modification was tolerated in the cellular assay, while modification of OG results in minimal cellular repair. High affinity for the mismatch and efficient base removal require the presence of OG. Taken together, these results suggest that the presence of OG is a critical feature for MutY to locate OG:A mismatches and select the appropriate adenines for excision to initiate repair in vivo prior to replication.The mismatch repair (MMR) pathway in E. coli relies on methylation at a GATC sequence to direct the repair machinery to remove the mismatched base on the newly synthesized strand. 1 However, almost two decades ago, an activity was detected in E. coli cell extracts that restored G:A mismatches to G:C matches and was insensitive to the methylation state of the template strand. [2][3][4] Concurrently, a mutator locus in E. coli (mutY) was identified that generated G:C → T:A transversion mutations. 5 It was later determined that the mutY gene product is an adenine glycosylase capable of removing adenines from G:A mismatches as the first step in base excision repair (BER). [6][7][8][9][10] The subsequent activity of downstream BER pathway enzymes, e.g. the AP endonuclease, deoxyribophosphate lyase, polymerase and ligase, restores the G:C base pair in a methylation-independent fashion. 11 MutY was also found to participate in the prevention of mutations caused by 7,8-dihydro-8-oxo-2′-deoxyguanosine (OG, 1) by removal of adenine from OG:A mismatches. 10,12,13,14 Polymerase misinsertion of dAMP opposite OG creates OG:A mismatches that can lead to formation of T:A base pairs upon a second round of replication. 12 Recently, MutY has been in the spotlight due to the correlation between inherited biallelic mutations in the gene encoding the human homologue of MutY (MUTYH) and colorectal cancer. 10,15,16 *Author to whom correspondence should be addressed. Email: david@chem.ucdavis.edu,. # These authors contributed equally to this manuscript. We have previously examined the features of mismatched substrates that are required for efficient lesion recognition and adenine excision by MutY using pre-steady state and singleturnover kinetics. [17][18][19] Pre-steady state experiments revealed that MutY has a high affinity for the product such that release of the DNA product is rate-limiting. 17,19,20 Moreover, the identity of the base opposite A greatly affects both the rate of product release as well as the intrinsic rate of adenine removal determined under single-turnover conditions....

show abstract

Insight into the functional consequences of hMYH variants associated with colorectal cancer: distinct differences in the adenine glycosylase activity and the response to AP endonucleases of Y150C and G365D murine MYH

Cited by 54 publications

References 48 publications

Consequences and Repair of Oxidative DNA Damage

Consequences and Repair of Oxidative DNA Damage

Biological contexts for DNA charge transport chemistry

Unnatural substrates reveal the importance of 8-oxoguanine for in vivo mismatch repair by MutY

Contact Info

Product

Resources

About