Toward a Detailed Understanding of Base Excision Repair Enzymes: Transition State and Mechanistic Analyses of N‐Glycoside Hydrolysis and N‐Glycoside Transfer

Berti, Paul J.; McCann, Joe A.B.

doi:10.1002/chin.200621267

Cited by 50 publications

(120 citation statements)

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“…Indeed, such a modification would be expected to modulate the pK a of N7, which is likely protonated as part of the base excision process. 30 Based on the positioning of a water molecule between N7 of A and Glu 43 of BsMY in the LRC X-ray structure, Glu 43 was proposed to serve as the general acid to protonate N7 of A via the water molecule as an important step in the dissociative mechanism (Fig. 1c).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…The nucleoside analogue FA is resistant to N-glycosidic bond hydrolysis due to the electron withdrawing nature of fluorine present at the C2′ position of the sugar, which destabilizes the oxocarbenium ion transition state. 30 MutY exhibits particularly high affinities for duplexes containing OG:FA bps (K d = 0.8 ± 0.4 nM). 25,31 The extents of conversion of OG:FA to G:C was significantly less than that observed with OG:A and OG:Z3 in the presence of MutY (57 ± 2 %).…”

Section: Cellular Repair Of Og:fa and G:fa Mismatchesmentioning

confidence: 99%

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

et al. 2007

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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....

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Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Section: Cellular Repair Of Og:fa and G:fa Mismatchesmentioning

confidence: 99%

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

et al. 2007

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“…ε (12) el,r component is also of stabilizing character for slide values greater than -1 Å, while the first-order electrostatic contribution is of negative sign only for slide values less than 0.5 Å. Opposite to ε (10) el and ε (20) disp , ∆E (2) ex−del and ε HL ex do not exhibit strong dependence on the slide parameter. Interestingly, the values of ε (10) el fall into very wide range, i.e.…”

Section: Accepted M Manuscriptmentioning

confidence: 86%

“…where ε (12) el,r denotes the term arising due to the dispersion and correlation corrections to the first-order electrostatic interacion, ε (20) disp is the dispersion contribution and ∆E (2) ex−del is the exchange-delocalization component.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…Non-covalent interactions are also involved in many important phenomena such as expression of the genetic code, DNA replication process and transcription. Furthermore, they play a key role in the recognition mechanism in protein-DNA complexes and intercalation of drugs into DNA [1][2][3]. Flexibility and conformational diversity of DNA and RNA can be attributed to hydrogen bonding (HB) and stacking interactions [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Theoretical insights into the nature of intermolecular interactions in cytosine dimer

Czyżnikowska¹,

Zaleśny²

2009

Biophysical Chemistry

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In this study we discuss stacking interactions in cytosine dimer in conformations appearing in B-DNA crystals. The variational-perturbational scheme was applied for decomposition of the intermolecular interaction energy at the MP2 level of theory. The significant influence of the mutual orientation of cytosine monomers was observed not only on the total intermolecular interaction energy but also on its components: Different components of intermolecular interaction energy depend in different manner on parameters describing mutual orientation of cytosine monomers.

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Targeting and processing of site‐specific DNA interstrand crosslinks

Vásquez

2010

Environ and Mol Mutagen

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DNA interstrand crosslinks (ICLs) are among the most cytotoxic types of DNA damage, and thus ICL-inducing agents such as cyclophosphamide, melphalan, cisplatin, psoralen and mitomycin C have been used clinically as anti-cancer drugs for decades. ICLs can also be formed endogenously as a consequence of cellular metabolic processes. ICL-inducing agents continue to be among the most effective chemotherapeutic treatments for many cancers; however, treatment with these agents can lead to secondary malignancies, in part due to mutagenic processing of the DNA lesions. The mechanisms of ICL repair have been characterized more thoroughly in bacteria and yeast than in mammalian cells. Thus, a better understanding the molecular mechanisms of ICL processing offers the potential to improve the efficacy of these drugs in cancer therapy. In mammalian cells it is thought that ICLs are repaired by the coordination of proteins from several pathways, including nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination (HR), translesion synthesis (TLS), and proteins involved in Fanconi anemia (FA). In this review, we focus on the potential functions of NER, MMR, and HR proteins in the repair of and response to ICLs in human cells and in mice. We will also discuss a unique approach, using psoralen covalently linked to triplex-forming oligonucleotides to direct ICLs to specific sites in the mammalian genome.

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Toward a Detailed Understanding of Base Excision Repair Enzymes: Transition State and Mechanistic Analyses of N‐Glycoside Hydrolysis and N‐Glycoside Transfer

Cited by 50 publications

References 1 publication

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

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

Theoretical insights into the nature of intermolecular interactions in cytosine dimer

Targeting and processing of site‐specific DNA interstrand crosslinks

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