| Superior removal of hydantoin lesions relative to other oxidized bases by the human DNA glycosylase hNEIL1. | |
| | |
MedLine Citation:
|
PMID: 18543945 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
The DNA glycosylase hNEIL1 initiates the base excision repair (BER) of a diverse array of lesions, including ring-opened purines and saturated pyrimidines. Of these, the hydantoin lesions, guanidinohydantoin (Gh) and the two diastereomers of spiroiminodihydantoin (Sp1 and Sp2), have garnered much recent attention due to their unusual structures, high mutagenic potential, and detection in cells. In order to provide insight into the role of repair, the excision efficiency by hNEIL1 of these hydantoin lesions relative to other known substrates was determined. Most notably, quantitative examination of the substrate specificity with hNEIL1 revealed that the hydantoin lesions are excised much more efficiently (>100-fold faster) than the reported standard substrates thymine glycol (Tg) and 5-hydroxycytosine (5-OHC). Importantly, the glycosylase and beta,delta-lyase reactions are tightly coupled such that the rate of the lyase activity does not influence the observed substrate specificity. The activity of hNEIL1 is also influenced by the base pair partner of the lesion, with both Gh and Sp removal being more efficient when paired with T, G, or C than when paired with A. Notably, the most efficient removal is observed with the Gh or Sp paired in the unlikely physiological context with T; indeed, this may be a consequence of the unstable nature of base pairs with T. However, the facile removal via BER in promutagenic base pairs that are reasonably formed after replication (such as Gh.G) may be a factor that modulates the mutagenic profile of these lesions. In addition, hNEIL1 excises Sp1 faster than Sp2, indicating the enzyme can discriminate between the two diastereomers. This is the first time that a BER glycosylase has been shown to be able to preferentially excise one diastereomer of Sp. This may be a consequence of the architecture of the active site of hNEIL1 and the structural uniqueness of the Sp lesion. These results indicate that the hydantoin lesions are the best substrates identified thus far for hNEIL1 and suggest that repair of these lesions may be a critical function of the hNEIL1 enzyme in vivo. |
| | |
Authors:
|
Nirmala Krishnamurthy; Xiaobei Zhao; Cynthia J Burrows; Sheila S David |
Related Documents
:
|
60865 - Endocrine function in patients with suprasellar and hypothalamic tumours. 21485765 - Hepatocellular carcinoma with polymyositis as an initial symptom: a case report. 20423685 - Incidental pituicytoma after accidental head trauma--case report and review of literature. 21433005 - Cytopathologic features and differential diagnostic considerations of primary lymphoepi... 22836795 - Hyperplastic intradiploic meningothelial tissue in the orbital roof mimicking metastati... 3549775 - Prostaglandin levels in a unicameral bone cyst treated by corticosteroid injection. |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-06-11 |
Journal Detail:
|
Title: Biochemistry Volume: 47 ISSN: 1520-4995 ISO Abbreviation: Biochemistry Publication Date: 2008 Jul |
Date Detail:
|
Created Date: 2008-07-01 Completed Date: 2008-07-16 Revised Date: 2011-03-16 |
Medline Journal Info:
|
Nlm Unique ID: 0370623 Medline TA: Biochemistry Country: United States |
Other Details:
|
Languages: eng Pagination: 7137-46 Citation Subset: IM |
Affiliation:
|
Department of Chemistry, University of Utah, 315 South, 1400 East, Salt Lake City, Utah 84112, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Base Sequence Binding Sites Computer Simulation DNA / chemistry, genetics DNA Damage* DNA Glycosylases / metabolism* DNA Repair* Enzyme Stability Guanidines / chemistry, metabolism* Guanosine / analogs & derivatives*, chemistry, metabolism Humans Hydantoins / chemistry, metabolism* Kinetics Molecular Sequence Data Oxidation-Reduction Purines / chemistry, metabolism* Pyrimidines / chemistry, metabolism* Spiro Compounds / chemistry, metabolism* Stereoisomerism |
| Grant Support | |
ID/Acronym/Agency:
|
CA90689/CA/NCI NIH HHS; R01 CA090689-01A1/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Guanidines; 0/Hydantoins; 0/Purines; 0/Pyrimidines; 0/Spiro Compounds; 0/guanidinohydantoin; 0/spiroiminodihydantoin; 118-00-3/Guanosine; 9007-49-2/DNA; EC 3.2.2.-/DNA Glycosylases; EC 3.2.2.-/NEIL1 protein, human |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Local RNA conformational dynamics revealed by 2-aminopurine solvent accessibility.
Next Document: Catalytic diversity of extended hammerhead ribozymes.