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Association between Transcriptional Activity, Local Chromatin Structure, and the Efficiencies of Both Subpathways of Nucleotide Excision Repair of Melphalan Adducts

¹ Institute of Biological Research and Biotechnology, National Hellenic Research Foundation; ² First Department of Propedeutic Medicine and ³ Department of Clinical Therapeutics, Athens University Medical School, Athens, Greece; and ⁴ Department of Toxicogenetics, Leiden University Medical Center, Leiden, the Netherlands

Requests for reprints: Vassilis L. Souliotis, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, Athens, Greece. Phone: 30-210-7273677; Fax: 30-210-7273677; E-mail: vls{at}eie.gr.

Key Words: gene-specific repair • chromatin condensation • transcriptional activity • transcription-coupled repair • global genome repair

The repair of melphalan-induced N-alkylpurine monoadducts and interstrand cross-links was examined in different repair backgrounds, focusing on four genes (β-actin, p53, N-ras, and -globin) with dissimilar transcription activities. Adducts were found to be substrates for both global genome repair (GGR) and transcription-coupled repair (TCR), with TCR being less efficient than GGR. In nucleotide excision repair–deficient cells, adducts accumulated to similar levels in all four genes. The repair efficiency in different gene loci varied in a qualitatively and quantitatively similar way in both GGR-deficient and TCR-deficient backgrounds and correlated with transcriptional activity and local chromatin condensation. No strand-specific repair was found in GGR⁺/TCR⁺ cells, implying that GGR dominated. Adducts were lost over two sharply demarcated phases: a rapid phase resulting in the removal within 1 hour of up to 80% of the adducts, and a subsequent phase with t_1/2 36 to 48 hours. Following pretreatment of cells with -amanitin, the rate of transcription, the state of chromatin condensation, and the repair efficiencies (both TCR and GGR) of the transcribed β-actin, p53, and N-ras genes became similar to those of the nontranscribed -globin gene. In conclusion, a continuous, parallel variation of the state of transcription and local chromatin condensation, on one hand, and the rates of both GGR and TCR, on the other hand, have been shown. [Cancer Res 2009;69(10):4424–33]