TY - JOUR
T1 - The cationic porphyrin TMPyP4 destabilizes the tetraplex form of the fragile X syndrome expanded sequence d(CGG)n
AU - Weisman-Shomer, Pnina
AU - Cohen, Esther
AU - Hershco, Inbal
AU - Khateb, Samer
AU - Wolfovitz-Barchad, Orit
AU - Hurley, Laurence H.
AU - Fry, Michael
N1 - Funding Information:
This study was supported by grants to M.F. from the US–Israel Binational Science Foundation, The Israel Science Foundation, the Conquer Fragile X Foundation Inc. and The Chief Scientist, Israel Ministry of Health.
PY - 2003/7/15
Y1 - 2003/7/15
N2 - 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.
AB - 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.
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U2 - 10.1093/nar/gkg453
DO - 10.1093/nar/gkg453
M3 - Article
C2 - 12853612
AN - SCOPUS:0242349126
SN - 0305-1048
VL - 31
SP - 3963
EP - 3970
JO - Nucleic acids research
JF - Nucleic acids research
IS - 14
ER -