Determinants in nuclease specificity of ape1 and ape2, human homologues of Escherichia coli exonuclease III 1 1Edited by J. Miller
Journal of Molecular Biology, ISSN: 0022-2836, Vol: 316, Issue: 3, Page: 853-866
2002
- 114Citations
- 65Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations114
- Citation Indexes114
- 114
- CrossRef79
- Captures65
- Readers65
- 64
Article Description
Abasic sites and non-conventional 3′-ends, e.g. 3′-oxidized fragments (including 3′-phosphate groups) and 3′-mismatched nucleotides, arise at significant frequency in the genome due to spontaneous decay, oxidation or replication errors. To avert the potentially mutagenic or cytotoxic effects of these chromosome modifications/intermediates, organisms are equipped with apurinic/apyrimidinic (AP) endonucleases and 3′-nucleases that initiate repair. Ape1, which shares homology with Escherichia coli exonuclease III (ExoIII), is the major abasic endonuclease in mammals and an important, yet selective, contributor to 3′-end processing. Mammals also possess a second protein (Ape2) with sequence homology to ExoIII, but this protein exhibits comparatively weak AP site-specific and 3′-nuclease activities. Prompted by homology modeling studies, we found that substitutions in the hydrophobic pocket of Ape1 (comprised of F266, W280 and L282) reduce abasic incision potency about fourfold to 450,000-fold, while introduction of an ExoIII-like pocket into Ape2 enhances its AP endonuclease function. We demonstrate that mutations at F266 and W280 of Ape1 increase 3′ to 5′ DNA exonuclease activity. These results, coupled with prior comparative sequence analysis, indicate that this active-site hydrophobic pocket influences the substrate specificity of a diverse set of sequence-related proteins possessing the conserved four-layered α/β-fold. Lastly, we report that wild-type Ape1 excises 3′-mismatched nucleotides at a rate up to 374-fold higher than correctly base-paired nucleotides, depending greatly on the structure and sequence of the DNA substrate, suggesting a novel, selective role for the human protein in 3′-mismatch repair.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0022283601953823; http://dx.doi.org/10.1006/jmbi.2001.5382; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0036303482&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/11866537; https://linkinghub.elsevier.com/retrieve/pii/S0022283601953823; https://dx.doi.org/10.1006/jmbi.2001.5382
Elsevier BV
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