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PMID: 12853612 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

The cationic porphyrin TMPyP4 destabilizes the tetraplex form of the fragile X syndrome expanded sequence d(CGG)n.

Nucleic acids research ·Vol. 31 ·No. 14 ·2003-07-15 ·Pages 3963-70

Weisman-Shomer P, Cohen E, Hershco I, Khateb S, Wolfovitz-Barchad O, Hurley LH, Fry M

Abstract

Fragile X syndrome, the most common cause of inherited mental retardation, is instigated by dynamic expansion of a d(CGG) trinucleotide repeat in the 5'-untranslated region of the first exon of the FMR1 gene, resulting in its silencing. The expanded d(CGG)(n) tract readily folds into hairpin and tetraplex structures which may contribute to the blocking of FMR1 transcription. In this work, we report that the cationic porphyrin 5,10,15,20-tetra(N-methyl-4-pyridyl)porphin (TMPyP4) effectively destabilizes in vitro the G'2 bimolecular tetraplex structure of d(CGG)(n) while it stabilizes the G'2 tetraplex form of the telomeric sequence d(TTAGGG)(2). Similarly to TMPyP4, the hnRNP-related protein CBF-A also destabilizes G'2 tetrahelical d(CGG)(n) while binding and stabilizing tetraplex telomeric DNA. We report that relative to each agent individually, successive incubation of G'2 d(CGG)(n) with TMPyP4 followed by exposure to CBF-A results in a nearly additive extent of disruption of this tetraplex form of the repeat sequence. Our observations open up the prospect of unfolding secondary structures of the expanded FMR1 d(CGG)(n) tract of fragile X cells by their exposure to low molecular size drugs or to proteins such as TMPyP4 or CBF-A.

MeSH Terms
Binding, Competitive DNA/chemistry,genetics,metabolism DNA Methylation DNA-Binding Proteins/chemistry,metabolism Fragile X Mental Retardation Protein Kinetics Nerve Tissue Proteins/genetics Nucleic Acid Conformation Nucleic Acid Denaturation Oligonucleotides/chemistry,genetics,metabolism Porphyrins/chemistry,metabolism RNA-Binding Proteins Repressor Proteins/chemistry,metabolism Temperature Trinucleotide Repeat Expansion/genetics
Chemicals
DNA-Binding Proteins Nerve Tissue Proteins Oligonucleotides Porphyrins RNA-Binding Proteins Repressor Proteins Fragile X Mental Retardation Protein tetra(4-N-methylpyridyl)porphine DNA
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Weisman-Shomer Pnina
Unit of Biochemistry, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, PO Box 9649, Haifa 31096, Israel.
Cohen Esther
Hershco Inbal
Khateb Samer
Wolfovitz-Barchad Orit
Hurley Laurence H
Fry Michael
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/gkg453
Published
2003-07-15
Pages
3963-70
Language
English
Region
England
NLM ID
0411011
PMCID
PMC165968
Subset
IM
External Links
PubMed source DOI: 10.1093/nar/gkg453 PMC Full Text View journal details
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