Structure of a DNA Duplex That Contains α-Anomeric Nucleotides and 3‘−3‘ and 5‘−5‘ Phosphodiester Linkages:  Coexistence of Parallel and Antiparallel DNA

Aramini, James M.; Kalisch, Bernd W.; Pon, R.T.; Sande, J.H. van de; Germann, Markus W.

doi:10.1021/bi960612p

Cited by 29 publications

(52 citation statements)

References 52 publications

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“…Our data appear to support a second model, capture-bend, where the MSH protein recognizes a dynamically flexible mismatched region provoking further protein conformational transitions that ultimately result in a [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] o DNA bend. The attraction of the capture-bend model is that the localized DNA flexibility surrounding a mismatch may be considered a fundamental recognition signal for MSH proteins; providing a simple explanation for the wide range of mismatches and lesions that activate MSH proteins.…”

Section: And References Therein)mentioning

confidence: 74%

“…The attraction of the capture-bend model is that the localized DNA flexibility surrounding a mismatch may be considered a fundamental recognition signal for MSH proteins; providing a simple explanation for the wide range of mismatches and lesions that activate MSH proteins. However, because it is doubtful that such localized DNA flexibility results in a spontaneous [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] o bend, further protein-induced DNA conformational transitions are probable. Alternatively, the [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] o bend observed in nondynamic structures might reflect an energy minimum that need not be entirely transited for MSH ATPase activation.…”

Section: And References Therein)mentioning

confidence: 99%

“…Melting temperatures for each of the mismatched duplexes were measured at 10 M total strand concentration in a buffer comprising 25 mM Hepes (pH 7.8), 100 mM NaCl, and 2 mM MgCl 2. The melting constants (T m, ⌬G, ⌬H) were obtained from 3 or more independent melting curves by using a 6-parameter fitting routine and assuming a 2-state, helix-coil transition (48).…”

Section: Uv Thermal Denaturationmentioning

confidence: 99%

“…The acquisition and processing parameters for the experiments for resonance assignment are analogous to those described in our earlier studies (48). 1 H and 31 P spectra were referenced to internal DSS and external 85% H 3PO4 (capillary in D2O).…”

Section: Uv Thermal Denaturationmentioning

confidence: 99%

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Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation

Mazurek

Johnson

Germann

et al. 2009

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

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Numerous DNA mismatches and lesions activate MutS homologue (MSH) ATPase activity that is essential for mismatch repair (MMR).We have found that a mismatch embedded in a nearest-neighbor sequence context containing symmetric 3-purines (2 ؋ 3-purines) enhanced, whereas symmetric 3-pyrimidines (2 ؋ 3-pyrimidines) reduced, hMSH2-hMSH6 ATPase activation. The 3-purine/pyrimidine effect was most evident for G-containing mispairs. A similar trend pervaded mismatch binding (K D) and the melting of unbound oligonucleotides (T m; ⌬G). However, these latter measures did not accurately predict the hierarchy of MSH ATPase activation. NMR studies of imino proton lifetime, solvent accessibility, and NOE connectivity suggest that sequence contexts that provoke improved MSH-activation displayed enhanced localized DNA flexibility: a dynamic DNA signature that may account for the wide range of lesions that activate MSH functions. Both MSH and MLH/PMS proteins contain consensus ATPbinding and hydrolysis (ATPase) activities required for MMR (3)(4)(5). A wide range of DNA lesions activate the MSH ATPase, including the 8 possible DNA mismatches, small insertion/deletion loops, and numerous damaged/modified nucleotides (6-9). This broad spectrum of DNA substrates is remarkable compared with glycosylases that also recognize nucleotide mismatch/lesions but demonstrate a very narrow range of substrate specificity (for review see ref. 10). Structural analysis of MSH proteins bound to several mismatched nucleotides (11) have revealed a number of consistent features including a 45-60°DNA bend at the mismatch and the formation of an incipient clamp in which the MSH protein both grasps and interrogates the mismatch (12)(13)(14). Yet all of the MSH structures contact and interrogate the mismatch region similarly regardless of the mismatch and/or MSH-adenosine nucleotide configuration (11). These results underline the lack of any molecular basis for the extensive range of MSH recognition or the transition from smooth to bent DNA.Both thermal instability and altered DNA flexibility of the mismatched region have been suggested factors that might influence MSH recognition (15,16). The idea that altered DNA flexibility may be a determinant is based on picosecond motions inferred from NMR 13 C relaxation data, although MSH recognition and activation or MMR appears to occur in the millisecond-minute time scale (16). Nucleotide-stacking interactions serve an important role in stabilizing DNA helical structure (17) and have been used to account for the thermal stability of mismatched DNA (16,18). The energetic components that account for altered DNA thermal stability and flexibility are controversial (19,20).The type of mismatched nucleotides, lesions, and nearestneighbor nucleotides influence MSH recognition and activation (21-23). Here, we have systematically examined the effect of nearest-neighbor sequence context on hMSH2-hMSH6 mispair recognition and ATPase activation as a model for understanding the extensive range of MSH recognition/activation pr...

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Section: And References Therein)mentioning

confidence: 74%

Section: And References Therein)mentioning

confidence: 99%

Section: Uv Thermal Denaturationmentioning

confidence: 99%

Section: Uv Thermal Denaturationmentioning

confidence: 99%

See 2 more Smart Citations

Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation

Mazurek

Johnson

Germann

et al. 2009

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

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“…The presence of an ␣-anomer in DNA does not affect base pairing or duplex stability but can affect sugar puckering (15).…”

Section: Hiv-1mentioning

confidence: 99%

Effect of DNA Modifications on DNA Processing by HIV-1 Integrase and Inhibitor Binding

Johnson

Sayer

Yagi

et al. 2006

Journal of Biological Chemistry

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Integration of the viral cDNA into host chromosomes is required for viral replication. Human immunodeficiency virus integrase catalyzes two sequential reactions, 3-processing (3-P) and strand transfer (ST). The first integrase inhibitors are undergoing clinical trial, but interactions of inhibitors with integrase and DNA are not well understood in the absence of a co-crystal structure. To increase our understanding of integrase interactions with DNA, we examined integrase catalysis with oligonucleotides containing DNA backbone, base, and groove modifications placed at unique positions surrounding the 3-processing site. 3-Processing was blocked with substrates containing constrained sugars and ␣-anomeric residues, suggesting that integrase requires flexibility of the phosphodiester backbone at the 3-P site. Of several benzo[a]pyrene 7,8-diol 9,10-epoxide (BaP DE) adducts tested, only the adduct in the minor groove at the 3-P site inhibited 3-P, suggesting the importance of the minor groove contacts for 3-P. ST occurred in the presence of bulky BaP DE DNA adducts attached to the end of the viral DNA suggesting opening of the active site for ST. Positionspecific effects of these BaP DE DNA adducts were found for inhibition of integrase by diketo acids. Together, these results demonstrate the importance of DNA structure and specific contacts with the viral DNA processing site for inhibition by integrase inhibitors. HIV-12 integrase (integrase) catalyzes insertion of cDNA copies of the viral genome into human chromosomes. Integrase binds to the ends ("att" sites) of each viral long terminal repeat (LTR) through sequence-specific recognition of a conserved 5Ј-CA within the sequence 5Ј-GCAGT. In the first of two reactions, integrase cleaves the 3Ј-ends of the viral DNA, releasing the terminal 5Ј-GT dinucleotide (3Ј-processing, 3Ј-P). In the second reaction, the free 3Ј-hydroxyl of the conserved adenine provides the nucleophile for insertion of the viral cDNA into a chromosome (strand transfer, ST). Gap repair and ligation between the viral and cellular DNA are performed by cellular factors. (For recent reviews and insights on integration, see Refs. 1-5.)Determination of the molecular interactions between integrase and its DNA substrates (viral and chromosomal DNA) has proven challenging, and a co-crystal of these components remains elusive. Biochemical studies have revealed contact points between the viral DNA and integrase. Integrase has an absolute requirement for the conserved 5Ј-CA adjoining the 3Ј-P site (underlined in Fig. 1A). The efficiency of 3Ј-P is also dramatically decreased by changes to the G immediately 5Ј to the conserved CA dinucleotide (6 -8). The conserved adenine, substituted by 5-iododeoxyuracil as a photocross-linker, forms a photocross-link to Lys-159 of integrase (9). Residue Lys-159 also contacts the phosphate 5Ј to the conserved deoxyadenosine (10). Mutagenesis showed that Tyr-143 and probably Gln-148 interact with the 5Ј-overhang resulting from 3Ј-P (9, 11). Moreover, disulfide cross-linking ...

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From Anionic to Cationic α‐Anomeric Oligodeoxynucleotides

Morvan

Debart

2010

Chemistry & Biodiversity

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Structure of a DNA Duplex That Contains α-Anomeric Nucleotides and 3‘−3‘ and 5‘−5‘ Phosphodiester Linkages: Coexistence of Parallel and Antiparallel DNA

Cited by 29 publications

References 52 publications

Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation

Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation

Effect of DNA Modifications on DNA Processing by HIV-1 Integrase and Inhibitor Binding

From Anionic to Cationic α‐Anomeric Oligodeoxynucleotides

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