Role of nucleotide excision repair in processing of O4-alkylthymines in human cells.

2.50
Hdl Handle:
http://hdl.handle.net/10541/96108
Title:
Role of nucleotide excision repair in processing of O4-alkylthymines in human cells.
Authors:
Klein, J C; Bleeker, M J; Roelen, H C; Rafferty, Joseph A; Margison, Geoffrey P; Brugghe, H F; Van den Elst, H; Van der Marel, G A; Van Boom, J H; Kriek, E
Abstract:
O4-Alkylthymines have been implicated as potential carcinogenic DNA lesions. We have studied the effects of O4-methylthymine, O4-ethylthymine, and O4-n-propylthymine in a model system in which a single lesion was located at a defined position on a SV40-based shuttle vector and have found large differences in the effects of these lesions in repair-proficient and nucleotide excision repair-deficient cells. In repair-competent human HeLa cells, normal fibroblasts, and XP-A (2OS) revertant cells, all 3 residues were highly mutagenic; a mutation frequency of approximately 20% was found for both O4-methylthymine and O4-ethylthymine, whereas that of O4-n-propylthymine was approximately 12%. These frequencies were independent of the activity of the O6-alkylguanine DNA alkyltransferase. All three O4-alkylthymines induced T-->C transitions exclusively. In nucleotide excision repair-deficient XP-A cells, however, these lesions were not mutagenic but strongly inhibited plasmid replication (> 90%). These results indicate that O4-alkylthymines are efficiently recognized by the nucleotide excision repair system and cause a complete cessation of plasmid replication if this system is deficient. Nevertheless, proficiency in the nucleotide excision repair pathway correlates with a high frequency of mutation induction by these lesions.
Affiliation:
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam.
Citation:
Role of nucleotide excision repair in processing of O4-alkylthymines in human cells. 1994, 269 (41):25521-8 J. Biol. Chem.
Journal:
The Journal of Biological chemistry
Issue Date:
14-Oct-1994
URI:
http://hdl.handle.net/10541/96108
PubMed ID:
7929253
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorKlein, J Cen
dc.contributor.authorBleeker, M Jen
dc.contributor.authorRoelen, H Cen
dc.contributor.authorRafferty, Joseph Aen
dc.contributor.authorMargison, Geoffrey Pen
dc.contributor.authorBrugghe, H Fen
dc.contributor.authorVan den Elst, Hen
dc.contributor.authorVan der Marel, G Aen
dc.contributor.authorVan Boom, J Hen
dc.contributor.authorKriek, Een
dc.date.accessioned2010-04-09T10:12:31Z-
dc.date.available2010-04-09T10:12:31Z-
dc.date.issued1994-10-14-
dc.identifier.citationRole of nucleotide excision repair in processing of O4-alkylthymines in human cells. 1994, 269 (41):25521-8 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid7929253-
dc.identifier.urihttp://hdl.handle.net/10541/96108-
dc.description.abstractO4-Alkylthymines have been implicated as potential carcinogenic DNA lesions. We have studied the effects of O4-methylthymine, O4-ethylthymine, and O4-n-propylthymine in a model system in which a single lesion was located at a defined position on a SV40-based shuttle vector and have found large differences in the effects of these lesions in repair-proficient and nucleotide excision repair-deficient cells. In repair-competent human HeLa cells, normal fibroblasts, and XP-A (2OS) revertant cells, all 3 residues were highly mutagenic; a mutation frequency of approximately 20% was found for both O4-methylthymine and O4-ethylthymine, whereas that of O4-n-propylthymine was approximately 12%. These frequencies were independent of the activity of the O6-alkylguanine DNA alkyltransferase. All three O4-alkylthymines induced T-->C transitions exclusively. In nucleotide excision repair-deficient XP-A cells, however, these lesions were not mutagenic but strongly inhibited plasmid replication (> 90%). These results indicate that O4-alkylthymines are efficiently recognized by the nucleotide excision repair system and cause a complete cessation of plasmid replication if this system is deficient. Nevertheless, proficiency in the nucleotide excision repair pathway correlates with a high frequency of mutation induction by these lesions.en
dc.language.isoenen
dc.subject.meshAlkyl and Aryl Transferases-
dc.subject.meshBase Sequence-
dc.subject.meshDNA Repair-
dc.subject.meshDNA Replication-
dc.subject.meshFibroblasts-
dc.subject.meshHela Cells-
dc.subject.meshHumans-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshMutagenesis, Site-Directed-
dc.subject.meshPlasmids-
dc.subject.meshSimian virus 40-
dc.subject.meshThymine-
dc.subject.meshTransfection-
dc.subject.meshTransferases-
dc.subject.meshXeroderma Pigmentosum-
dc.titleRole of nucleotide excision repair in processing of O4-alkylthymines in human cells.en
dc.typeArticleen
dc.contributor.departmentDivision of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam.en
dc.identifier.journalThe Journal of Biological chemistryen
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