Solution Structure of a DNA Duplex Containing an α-Anomeric Adenosine: Insights into Substrate Recognition by Endonuclease IV

Aramini, James M.; Cleaver, Stephen H.; Pon, Richard T.; Cunningham, Richard P.; Germann, Markus W.

doi:10.1016/j.jmb.2004.02.035

Cited by 35 publications

(56 citation statements)

References 53 publications

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“…The phosphodiester backbone could be assigned by using 31 (37,38). Although nonstandard phosphodiester conformations could conceptually serve as markers for mismatch recognition, they are unlikely to drive MSH recognition/activation since we observe the B II conformation in both well and poorly recognized sequence contexts (Figs.…”

Section: Resultsmentioning

confidence: 88%

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: Resultsmentioning

confidence: 88%

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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“…Notably, there is a significant pocket next to the active site that is present in both Nfo and APE1. We postulated that this pocket may allow the nucleotide incision repair activity and the requisite space for binding a base, albeit a non-canonical base, but simple modeling with a nucleotide incision repair substrate, an ␣-anomeric adenosine, did not position the base in that pocket (72). Perhaps this pocket has convergently evolved for a yet unrecognized functionality.…”

Section: Resultsmentioning

confidence: 99%

Conserved Structural Chemistry for Incision Activity in Structurally Non-homologous Apurinic/Apyrimidinic Endonuclease APE1 and Endonuclease IV DNA Repair Enzymes

Tsutakawa

Shin

Mol

et al. 2013

Journal of Biological Chemistry

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165

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Background: DNA apurinic/apyrimidinic (AP) sites are toxic and mutagenic if unrepaired by AP endonucleases. Results: Structural, mutational, and computational analyses of prototypic AP endonucleases APE1 and Nfo identify surprising similarities. Conclusion: APE1 and Nfo reveal functional equivalences illuminating their catalytic reaction. Significance: A conserved catalytic geometry is specific to AP site removal despite different enzyme structures and metal ions.

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“…[38] To understand signaling and recruitment of the repair enzyme Endo IV, we determined the structural consequences of a single α-anomeric adenosine in a DNA duplex substrate for Endo IV. [40] Interestingly, unlike the inclusion of an αanomeric thymidine, incorporation of an α-A residue revealed only a slightly lower stability compared to the unmodified control. This is further supported by the NMR solution structure of the DNA decamer, which reveals that the lesion is intrahelical and stacked within the duplex in a reverse Watson-Crick fashion.…”

Section: Nmr Structural Studiesmentioning

confidence: 96%

Unusual DNA Structure and DNA Damage Recognition: Structure and Dynamic Markers

Germann¹,

Johnson²,

Spring³

2009

Chimia

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Nucleic acids play a central role in many biological processes, including information storage, gene expression, serving as messengers or structural components and even catalysis. Their diverse roles have made them targets of interest to diagnose and treat an array of human disorders such as infections, degenerative diseases and cancer. Nature has evolved proteins and ligands that recognize specific nucleic acid sequences or structures and control their function, demonstrating that this can be efficiently accomplished. This has led to the development of wide variety of synthetic molecules that selectively bind to nucleic acids. In turn, this has precipitated numerous studies which showed that nucleic acid structures and their dynamic properties must be understood in order to efficiently target specific sequences or structures.

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Solution Structure of a DNA Duplex Containing an α-Anomeric Adenosine: Insights into Substrate Recognition by Endonuclease IV

Cited by 35 publications

References 53 publications

Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation

Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation

Conserved Structural Chemistry for Incision Activity in Structurally Non-homologous Apurinic/Apyrimidinic Endonuclease APE1 and Endonuclease IV DNA Repair Enzymes

Unusual DNA Structure and DNA Damage Recognition: Structure and Dynamic Markers

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