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XRCC1 deficiency influences the cytotoxicity and the genomic instability induced by Me-lex, a specific inducer of N3-methyladenine.

Abstract
Me-lex is a sequence-specific alkylating agent synthesized to preferentially (>90%) generate N3-methyladenine (3-mA) in the minor groove of double-strand DNA, in A-T rich regions. In this paper we investigated the effect of XRCC1 deficiency in the processing of 3-mA adducts generated by Me-lex, through the molecular analysis of the Hprt mutations and the evaluation of cytogenetic end points such as sister chromatid exchanges (SCEs), micronuclei (MN) and nucleus fragmentation. EM-C11 cells, deficient in XRCC1 activity, showed a 2.5-fold higher sensitivity to the toxicity of Me-lex compared to the DNA repair proficient parental CHO-9 cells, but were not hyper mutable. The spontaneous mutation spectrum at the Hprt locus generated in EM-C11 cells revealed a high percentage of genomic deletions. After Me-lex treatment, the percentage of genomic deletions did not increase, but a class of mutations which appeared to target regulatory regions of the gene significantly increased (p=0.0277), suggesting that non-coding Hprt genomic sequences represent a strong target for the rare mutations induced by Me-lex. The number of SCEs per chromosome increased 3-fold above background in 50mucapital EM, Cyrillic Me-lex treated CHO-9 cells, while at higher Me-lex concentrations a sharp increase in the percentage of MN and fragmented nuclei was observed. In EM-C11 cells the background level of SCEs (0.939+/-0.182) was approximately 10-fold higher than in CHO-9 (0.129+/-0.027) and higher levels of multinucleated cells and MN were also found. In EM-C11, even low doses of Me-lex (25microM) led to a significant increase in genomic damage. These results indicate that XRCC1 deficiency can lead to genomic instability even in the absence of an exogenous genotoxic insult and low levels of Me-lex-induced lesions, i.e., 3-mA and/or a BER intermediate, can exacerbate this instability.
AuthorsDebora Russo, Gilberto Fronza, Laura Ottaggio, Paola Monti, Chiara Perfumo, Alberto Inga, Prema Iyer, Barry Gold, Paola Menichini
JournalDNA repair (DNA Repair (Amst)) Vol. 9 Issue 7 Pg. 728-36 (Jul 1 2010) ISSN: 1568-7856 [Electronic] Netherlands
PMID20471330 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright2010 Elsevier B.V. All rights reserved.
Chemical References
  • Alkylating Agents
  • DNA-Binding Proteins
  • Mutagens
  • X-ray repair cross complementing protein 1
  • methyl lexitropsin
  • 3-methyladenine
  • Netropsin
  • Adenine
Topics
  • Adenine (analogs & derivatives, metabolism)
  • Alkylating Agents (pharmacology)
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • DNA Damage (genetics)
  • DNA-Binding Proteins (genetics)
  • Genomic Instability (genetics)
  • Mutagens (pharmacology)
  • Netropsin (analogs & derivatives, pharmacology)
  • Sequence Deletion

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