The repair of melphalan-induced DNA adducts in the transcribed strand of active genes is subject to a strong polarity effect.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Kyrtopoulos, Soterios A.
Sfikakis, Petros P.
Dimopoulos, Meletios A.
Souliotis, Vassilis L.
MetadataShow full item record
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.
CitationMutat. Res. 2011, 714 (1-2):78-87
SponsorsThis work was partly supported by the ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility) Network of Excellence of the European Union (contract no. 513943).
- Preferential in vivo DNA repair of melphalan-induced damage in human genes is greatly affected by the local chromatin structure.
- Authors: Souliotis VL, Dimopoulos MA, Episkopou HG, Kyrtopoulos SA, Sfikakis PP
- Issue date: 2006 Aug 13
- Association between transcriptional activity, local chromatin structure, and the efficiencies of both subpathways of nucleotide excision repair of melphalan adducts.
- Authors: Episkopou H, Kyrtopoulos SA, Sfikakis PP, Fousteri M, Dimopoulos MA, Mullenders LH, Souliotis VL
- Issue date: 2009 May 15
- Extent of damage and repair in the p53 tumor-suppressor gene after treatment of myeloma patients with high-dose melphalan and autologous blood stem-cell transplantation is individualized and may predict clinical outcome.
- Authors: Dimopoulos MA, Souliotis VL, Anagnostopoulos A, Papadimitriou C, Sfikakis PP
- Issue date: 2005 Jul 1
- Gene-specific formation and repair of DNA monoadducts and interstrand cross-links after therapeutic exposure to nitrogen mustards.
- Authors: Souliotis VL, Dimopoulos MA, Sfikakis PP
- Issue date: 2003 Oct 1
- Enhanced sensitivity to anti-benzo(a)pyrene-diol-epoxide DNA damage correlates with decreased global genomic repair attributable to abrogated p53 function in human cells.
- Authors: Wani MA, Zhu Q, El-Mahdy M, Venkatachalam S, Wani AA
- Issue date: 2000 Apr 15