The repair of melphalan-induced DNA adducts in the transcribed strand of active genes is subject to a strong polarity effect.

2.50
Hdl Handle:
http://hdl.handle.net/10146/192391
Title:
The repair of melphalan-induced DNA adducts in the transcribed strand of active genes is subject to a strong polarity effect.
Authors:
Episkopou, Hara; Kyrtopoulos, Soterios A.; Sfikakis, Petros P.; Dimopoulos, Meletios A.; Souliotis, Vassilis L.
Abstract:
To investigate the mechanisms of the therapeutic action and drug resistance to the nitrogen mustard melphalan, melphalan-induced DNA damage repair and chromatin structure were examined along the p53, N-ras and d-globin gene loci in cells carrying different repair activities. In nucleotide excision repair-deficient XP-A cells, similar levels of adducts were found in all fragments examined, indicating uniform distribution of DNA damage. In both, repair-proficient CS-B and XP-C cells, faster repair was observed in regions inside the transcribed N-ras and p53 genes, compared to regions on both sides outside of the genes, while no such difference was observed for the inactive d-globin gene. Moreover, very fast adduct repair on the transcribed strand of the active genes was seen immediately downstream of the transcription start site, together with a steeply decreasing gradient of repair efficiency along the gene towards the 3'-end. In all cells analyzed, the above variation in DNA repair efficiency was paralleled exactly by the variation in the degree of local chromatin condensation, more relaxed chromatin being associated with faster repair. Similar results were obtained using peripheral blood mononuclear cells from healthy volunteers, suggesting that the existence of a repair gradient along transcribed genes may be a universal phenomenon. In conclusion, these findings demonstrate that the repair of melphalan adducts in the transcribed strand of active genes is subject to a strong polarity effect arising from variations in the chromatin structure.
Citation:
Mutat. Res. 2011, 714 (1-2):78-87
Journal:
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
Issue Date:
1-Sep-2011
URI:
http://hdl.handle.net/10146/192391
DOI:
10.1016/j.mrfmmm.2011.06.012
PubMed ID:
21762707
Additional Links:
http://www.sciencedirect.com/science/article/pii/S0027510711001540
Type:
Article
Language:
en
ISSN:
0027-5107
Sponsors:
This work was partly supported by the 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.authorDimopoulos, Meletios A.en
dc.contributor.authorSouliotis, Vassilis L.en
dc.date.accessioned2011-11-29T14:26:11Z-
dc.date.available2011-11-29T14:26:11Z-
dc.date.issued2011-09-01-
dc.identifier.citationMutat. Res. 2011, 714 (1-2):78-87en
dc.identifier.issn0027-5107-
dc.identifier.pmid21762707-
dc.identifier.doi10.1016/j.mrfmmm.2011.06.012-
dc.identifier.urihttp://hdl.handle.net/10146/192391-
dc.description.abstractTo investigate the mechanisms of the therapeutic action and drug resistance to the nitrogen mustard melphalan, melphalan-induced DNA damage repair and chromatin structure were examined along the p53, N-ras and d-globin gene loci in cells carrying different repair activities. In nucleotide excision repair-deficient XP-A cells, similar levels of adducts were found in all fragments examined, indicating uniform distribution of DNA damage. In both, repair-proficient CS-B and XP-C cells, faster repair was observed in regions inside the transcribed N-ras and p53 genes, compared to regions on both sides outside of the genes, while no such difference was observed for the inactive d-globin gene. Moreover, very fast adduct repair on the transcribed strand of the active genes was seen immediately downstream of the transcription start site, together with a steeply decreasing gradient of repair efficiency along the gene towards the 3'-end. In all cells analyzed, the above variation in DNA repair efficiency was paralleled exactly by the variation in the degree of local chromatin condensation, more relaxed chromatin being associated with faster repair. Similar results were obtained using peripheral blood mononuclear cells from healthy volunteers, suggesting that the existence of a repair gradient along transcribed genes may be a universal phenomenon. In conclusion, these findings demonstrate that the repair of melphalan adducts in the transcribed strand of active genes is subject to a strong polarity effect arising from variations in the chromatin structure.en
dc.description.sponsorshipThis work was partly supported by the ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility) Network of Excellence of the European Union (contract no. 513943).en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S0027510711001540en
dc.subjectRegion-specific repairen
dc.subjectChromatin condensationen
dc.subjectMelphalan adductsen
dc.subjectRepair gradienten
dc.subject.meshCell Line-
dc.subject.meshCell Polarity-
dc.subject.meshChromatin Assembly and Disassembly-
dc.subject.meshDNA Adducts-
dc.subject.meshDNA Damage-
dc.subject.meshDNA Repair-
dc.subject.meshFibroblasts-
dc.subject.meshGenes, p53-
dc.subject.meshGenes, ras-
dc.subject.meshGlobins-
dc.subject.meshHumans-
dc.subject.meshLeukocytes, Mononuclear-
dc.subject.meshMelphalan-
dc.subject.meshTranscription, Genetic-
dc.titleThe repair of melphalan-induced DNA adducts in the transcribed strand of active genes is subject to a strong polarity effect.en
dc.typeArticleen
dc.identifier.journalMutation Research/Fundamental and Molecular Mechanisms of Mutagenesisen
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