Association between transcriptional activity, local chromatin structure, and the efficiencies of both subpathways of nucleotide excision repair of melphalan adducts.

2.50
Hdl Handle:
http://hdl.handle.net/10146/113728
Title:
Association between transcriptional activity, local chromatin structure, and the efficiencies of both subpathways of nucleotide excision repair of melphalan adducts.
Authors:
Episkopou, Hara; Kyrtopoulos, Soterios A.; Sfikakis, Petros P.; Fousteri, Maria; Dimopoulos, Meletios A.; Mullenders, Leon H. F.; Souliotis, Vassilis L.
Abstract:
The repair of melphalan-induced N-alkylpurine monoadducts and interstrand cross-links was examined in different repair backgrounds, focusing on four genes (beta-actin, p53, N-ras, and delta-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 approximately 80% of the adducts, and a subsequent phase with t(1/2) approximately 36 to 48 hours. Following pretreatment of cells with alpha-amanitin, the rate of transcription, the state of chromatin condensation, and the repair efficiencies (both TCR and GGR) of the transcribed beta-actin, p53, and N-ras genes became similar to those of the nontranscribed delta-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.
Citation:
Cancer Res. 2009, 69 (10):4424-4433
Journal:
Cancer Research
Issue Date:
15-May-2009
URI:
http://hdl.handle.net/10146/113728
DOI:
10.1158/0008-5472.CAN-08-3489
PubMed ID:
19417135
Additional Links:
http://cancerres.aacrjournals.org/content/69/10/4424.long
Type:
Article
Language:
en
ISSN:
1538-7445
Sponsors:
Grant support: ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility) Network of Excellence of the European Union (contract no. 513943).
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorEpiskopou, Haraen
dc.contributor.authorKyrtopoulos, Soterios A.en
dc.contributor.authorSfikakis, Petros P.en
dc.contributor.authorFousteri, Mariaen
dc.contributor.authorDimopoulos, Meletios A.en
dc.contributor.authorMullenders, Leon H. F.en
dc.contributor.authorSouliotis, Vassilis L.en
dc.date.accessioned2010-10-22T14:22:20Z-
dc.date.available2010-10-22T14:22:20Z-
dc.date.issued2009-05-15-
dc.identifier.citationCancer Res. 2009, 69 (10):4424-4433en
dc.identifier.issn1538-7445-
dc.identifier.pmid19417135-
dc.identifier.doi10.1158/0008-5472.CAN-08-3489-
dc.identifier.urihttp://hdl.handle.net/10146/113728-
dc.description.abstractThe repair of melphalan-induced N-alkylpurine monoadducts and interstrand cross-links was examined in different repair backgrounds, focusing on four genes (beta-actin, p53, N-ras, and delta-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 approximately 80% of the adducts, and a subsequent phase with t(1/2) approximately 36 to 48 hours. Following pretreatment of cells with alpha-amanitin, the rate of transcription, the state of chromatin condensation, and the repair efficiencies (both TCR and GGR) of the transcribed beta-actin, p53, and N-ras genes became similar to those of the nontranscribed delta-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.en
dc.description.sponsorshipGrant support: ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility) Network of Excellence of the European Union (contract no. 513943).en
dc.language.isoenen
dc.relation.urlhttp://cancerres.aacrjournals.org/content/69/10/4424.longen
dc.subjectAntineoplastic Agentsen
dc.subjectDNA Damageen
dc.subjectDNA Repairen
dc.subjectCell Survivalen
dc.subjectChromatinen
dc.subjectGenes, p53en
dc.subjectTranscription, Geneticen
dc.subjectHumansen
dc.subject.meshActins-
dc.subject.meshAntineoplastic Agents, Alkylating-
dc.subject.meshCell Survival-
dc.subject.meshChromatin-
dc.subject.meshDNA Damage-
dc.subject.meshDNA Repair-
dc.subject.meshFibroblasts-
dc.subject.meshGenes, p53-
dc.subject.meshGenes, ras-
dc.subject.meshHumans-
dc.subject.meshKinetics-
dc.subject.meshMelphalan-
dc.subject.meshTranscription, Genetic-
dc.subject.meshdelta-Globins-
dc.titleAssociation between transcriptional activity, local chromatin structure, and the efficiencies of both subpathways of nucleotide excision repair of melphalan adducts.en
dc.typeArticleen
dc.identifier.journalCancer Researchen
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