DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA•TTC repeats in Friedreich's ataxia

被引:108
作者
Burnett, Ryan
Melander, Christian
Puckett, James W.
Son, Leslie S.
Wells, Robert D.
Dervan, Peter B.
Gottesfeld, Joel M.
机构
[1] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[2] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
[3] Texas A&M Univ, Inst Biosci & Technol, Ctr Genome Res, Syst Hlth Sci Ctr, Houston, TX 77030 USA
关键词
gene regulation; triplet repeat expansion; frataxin;
D O I
10.1073/pnas.0604939103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The DNA abnormality found in 98% of Friedreich's ataxia (FRDA) patients is the unstable hyperexpansion of a GAA(.)TTC triplet repeat in the first intron of the frataxin gene. Expanded GAA.TTC repeats result in decreased transcription and reduced levels of frataxin protein in affected individuals. P-Alanine-linked pyrrole-imidazole polyamides bind GAA(.)TTC tracts with high affinity and disrupt the intramolecular DNA-DNA-associated region of the sticky-DNA conformation formed by long GAA(.)TTC repeats. Fluorescent polyamide-Bodipy conjugates localize in the nucleus of a lymphoid cell line derived from a FRDA patient. The synthetic ligands increase transcription of the frataxin gene in cell culture, resulting in increased levels of frataxin protein. DNA microarray analyses indicate that a limited number of genes are significantly affected in FRDA cells. Polyamides may increase transcription by altering the DNA conformation of genes harboring long GAA(.)TTC repeats or by chromatin opening.
引用
收藏
页码:11497 / 11502
页数:6
相关论文
共 38 条
[1]   Solid phase synthesis of polyamides containing imidazole and pyrrole amino acids [J].
Baird, EE ;
Dervan, PB .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1996, 118 (26) :6141-6146
[2]   Nuclear localization of pyrrole-imidazole polyamide-fluorescein conjugates in cell culture [J].
Best, TP ;
Edelson, BS ;
Nickols, NG ;
Dervan, PB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (21) :12063-12068
[3]   The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure [J].
Bidichandani, SI ;
Ashizawa, T ;
Patel, PI .
AMERICAN JOURNAL OF HUMAN GENETICS, 1998, 62 (01) :111-121
[4]   Displacement of D1, HP1 and topoisomerase II from satellite heterochromatin by a specific polyamide [J].
Blattes, Roxane ;
Monod, Caroline ;
Susbielle, Guillaume ;
Cuvier, Olivier ;
Wu, Jian-hong ;
Hsieh, Tao-shih ;
Laemmli, Ulrich K. ;
Kas, Emmanuel .
EMBO JOURNAL, 2006, 25 (11) :2397-2408
[5]   A comparison of normalization methods for high density oligonucleotide array data based on variance and bias [J].
Bolstad, BM ;
Irizarry, RA ;
Åstrand, M ;
Speed, TP .
BIOINFORMATICS, 2003, 19 (02) :185-193
[6]   Friedreich's ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion [J].
Campuzano, V ;
Montermini, L ;
Molto, MD ;
Pianese, L ;
Cossee, M ;
Cavalcanti, F ;
Monros, E ;
Rodius, F ;
Duclos, F ;
Monticelli, A ;
Zara, F ;
Canizares, J ;
Koutnikova, H ;
Bidichandani, SI ;
Gellera, C ;
Brice, A ;
Trouillas, P ;
DeMichele, G ;
Filla, A ;
DeFrutos, R ;
Palau, F ;
Patel, PI ;
DiDonato, S ;
Mandel, JL ;
Cocozza, S ;
Koenig, M ;
Pandolfo, M .
SCIENCE, 1996, 271 (5254) :1423-1427
[7]   Expression profiling in multistage hepatocarcinogenesis: Identification of HSP70 as a molecular marker of early hepatocellular carcinoma [J].
Chuma, M ;
Sakamoto, M ;
Yamazaki, K ;
Ohta, T ;
Ohki, M ;
Asaka, M ;
Hirohashi, S .
HEPATOLOGY, 2003, 37 (01) :198-207
[8]   Expansion of GAA triplet repeats in the human genome:: unique origin of the FRDA mutation at the center of an Alu [J].
Clark, RM ;
Dalgliesh, GL ;
Endres, D ;
Gomez, M ;
Taylor, J ;
Bidichandani, SI .
GENOMICS, 2004, 83 (03) :373-383
[9]   Gene expression profiling in frataxin deficient mice: Microarray evidence for significant expression changes without detectable neurodegeneration [J].
Coppola, G ;
Choi, SH ;
Santos, MM ;
Miranda, CJ ;
Tentler, D ;
Wexler, EM ;
Pandolfo, M ;
Geschwind, DH .
NEUROBIOLOGY OF DISEASE, 2006, 22 (02) :302-311
[10]   Recognition of the DNA minor groove by pyrrole-imidazole polyamides [J].
Dervan, PB ;
Edelson, BS .
CURRENT OPINION IN STRUCTURAL BIOLOGY, 2003, 13 (03) :284-299