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Titolo:
Repair of O-6-methylguanine is not affected by thymine base pairing and the presence of MMR proteins
Autore:
Lips, J; Kaina, B;
Indirizzi:
Univ Mainz, Inst Toxicol, Div Appl Toxicol, D-55131 Mainz, Germany Univ Mainz Mainz Germany D-55131 iv Appl Toxicol, D-55131 Mainz, Germany
Titolo Testata:
MUTATION RESEARCH-DNA REPAIR
fascicolo: 1-2, volume: 487, anno: 2001,
pagine: 59 - 66
SICI:
0921-8777(20011101)487:1-2<59:ROOINA>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
SISTER-CHROMATID EXCHANGES; ALKYLATING-AGENTS; METHYLTRANSFERASE MGMT; MISMATCH REPAIR; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; CHROMOSOME-ABERRATIONS; TRANSGENIC MICE; HUMAN TUMOR; HUMAN-CELLS; DNA;
Keywords:
MGMT; O-6-methylguanine; methylation; DNA repair; mismatch repair;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
30
Recensione:
Indirizzi per estratti:
Indirizzo: Kaina, B Univ Mainz, Inst Toxicol, Div Appl Toxicol, Obere Zahlbacher St 67, D-55131 Mainz, Germany Univ Mainz Obere Zahlbacher St 67 Mainz Germany D-55131 Germany
Citazione:
J. Lips e B. Kaina, "Repair of O-6-methylguanine is not affected by thymine base pairing and the presence of MMR proteins", MUT R-DNA R, 487(1-2), 2001, pp. 59-66

Abstract

Methylation at the O-6-position of guanine (O-6-MeG) by alkylating agents is efficiently removed by O-6-Methylguanine-DNA methyltransferase (MGMT), preventing from cytotoxic, mutagenic, clastogenic and carcinogenic effects Of O-6 O-6-MeG-inducing agents. If O-6-MeG is not removed from DNA prior to replication, thymine will be incorporated instead of cytosine opposite the O-6-MeG lesion. This mismatch is recognized and processed by mismatch repair (MMR) proteins which are known to be involved in triggering the cytotoxicand genotoxic response of cells upon methylation. In this work we addressed three open questions. (1) Is MGMT able to repair O-6-MeG mispaired with thymine (O-6-MeG/T)? (2) Do MMR proteins interfere with the repair of O-6-MeG/T by MGMT? (3) Does MGMT show a protective effect if it is expressed after replication of -MeG/T mismatches are as DNA containing O-6-MeG? Using an in vitro assay we show that oligonucleotides containing O-6 efficient as oligonucleotides containing O-6-MeG/C in competing for MGMT repair activity, indicating that O-6-MeG mispaired with thymine is still subject to repair by MGMT. The addition of MMR proteins from nuclear extracts, or of recombinant MutS alpha, to the in vitro repair assay did not affect the repair of O-6-MeG/T lesions by MGMT. This indicates that the presence of MutS alpha still allows access of MGMT to O-6-MeG/T lesions. To elucidate the protective effect of MGMT in the first and second replication cycle after N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatment, MGMT transfected CHO cells were synchronized and MGMT was inactivated by pulse-treatment with O-6-benzylguanine (O-6-BG). Thereafter, the recovered cells were treated with MNNG and subjected to clonogenic survival assays. Cells which expressed MGMT in the first and second cell cycle were more resistant than cells which expressed MGMT only in the second (post-treatment) cell cycle. Cells which did not express MGMT in both cell cycles were most sensitive. This indicates that repair of O-6-MeG can occur both in the first and second cell cycle after alkylation protecting cells from the killing effect of the lesion. (C) 2001 Elsevier Science B.V. Ail rights reserved.

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Documento generato il 06/07/20 alle ore 08:03:56