Nucleic Acids Research, 2000, Vol. 28, No. 14 2815-2822
© 2000 Oxford University Press
The GAA•TTC triplet repeat expanded in Friedreich’s ataxia impedes transcription elongation by T7 RNA polymerase in a length and supercoil dependent manner
Section on Genomic Structure and Function, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830, USA
Large expansions of the trinucleotide repeat GAA•TTC within the first intron of the X25 (frataxin) gene cause Friedreich’s ataxia, the most common inherited ataxia. Expansion leads to reduced levels of frataxin mRNA in affected individuals. Here we show that GAA•TTC tracts, in the absence of any other frataxin gene sequences, can reduce the amount of GAA-containing transcript produced in a defined in vitro transcription system. This effect is due to an impediment to elongation that forms in the GAA•TTC tract during transcription, a phenomenon that is exacerbated by both superhelical stress and increased tract length. On supercoiled templates the major truncations of the GAA-containing transcripts occur in the distal (3') end of the GAA repeat. To account for these observations we present a model in which an RNA polymerase advancing within a long GAA•TTC tract initiates the transient formation of an R•R•Y intramolecular DNA triplex. The non-template (GAA) strand folds back creating a loop in the template strand, and the polymerase is paused at the distal triplex–duplex junction.
* To whom correspondence should be addressed at: Building 8, Room 202, National Institutes of Health, 8 CENTER DR MSC 0830, Bethesda, MD 20892-0830, USA. Tel: +1 301 594 5259; Fax: +1 301 402 0053; Email: grabczyk@helix.nih.gov
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Kumari and K. Usdin Chromatin Remodeling in the Noncoding Repeat Expansion Diseases J. Biol. Chem., March 20, 2009; 284(12): 7413 - 7417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sureshkumar, M. Todesco, K. Schneeberger, R. Harilal, S. Balasubramanian, and D. Weigel A Genetic Defect Caused by a Triplet Repeat Expansion in Arabidopsis thaliana Science, February 20, 2009; 323(5917): 1060 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Soragni, D. Herman, S. Y. R. Dent, J. M. Gottesfeld, R. D. Wells, and M. Napierala Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia Nucleic Acids Res., November 1, 2008; 36(19): 6056 - 6065. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Usdin The biological effects of simple tandem repeats: Lessons from the repeat expansion diseases Genome Res., July 1, 2008; 18(7): 1011 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. V. Ditlevson, S. Tornaletti, B. P. Belotserkovskii, V. Teijeiro, G. Wang, K. M. Vasquez, and P. C. Hanawalt Inhibitory effect of a short Z-DNA forming sequence on transcription elongation by T7 RNA polymerase Nucleic Acids Res., June 1, 2008; 36(10): 3163 - 3170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Wells DNA triplexes and Friedreich ataxia FASEB J, June 1, 2008; 22(6): 1625 - 1634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tornaletti, S. Park-Snyder, and P. C. Hanawalt G4-forming Sequences in the Non-transcribed DNA Strand Pose Blocks to T7 RNA Polymerase and Mammalian RNA Polymerase II J. Biol. Chem., May 9, 2008; 283(19): 12756 - 12762. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Al-Mahdawi, R. M. Pinto, O. Ismail, D. Varshney, S. Lymperi, C. Sandi, D. Trabzuni, and M. Pook The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues Hum. Mol. Genet., March 1, 2008; 17(5): 735 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Pollard, R. L. Bourn, and S. I. Bidichandani Repair of DNA double-strand breaks within the (GAA*TTC)n sequence results in frequent deletion of the triplet-repeat sequence Nucleic Acids Res., February 2, 2008; 36(2): 489 - 500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Patel, A. T. Phan, and V. Kuryavyi Human telomere, oncogenic promoter and 5'-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics Nucleic Acids Res., December 3, 2007; 35(22): 7429 - 7455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Pollard, Y. K. Chutake, P. M. Rindler, and S. I. Bidichandani Deficiency of RecA-dependent RecFOR and RecBCD pathways causes increased instability of the (GAA{middle dot}TTC)n sequence when GAA is the lagging strand template Nucleic Acids Res., November 29, 2007; 35(20): 6884 - 6894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. P. Belotserkovskii, E. De Silva, S. Tornaletti, G. Wang, K. M. Vasquez, and P. C. Hanawalt A Triplex-forming Sequence from the Human c-MYC Promoter Interferes with DNA Transcription J. Biol. Chem., November 2, 2007; 282(44): 32433 - 32441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Grabczyk, M. Mancuso, and M. C. Sammarco A persistent RNA{middle dot}DNA hybrid formed by transcription of the Friedreich ataxia triplet repeat in live bacteria, and by T7 RNAP in vitro Nucleic Acids Res., August 13, 2007; 35(16): 5351 - 5359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Greene, L. Mahishi, A. Entezam, D. Kumari, and K. Usdin Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia Nucleic Acids Res., May 11, 2007; 35(10): 3383 - 3390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Krasilnikova, M. L. Kireeva, V. Petrovic, N. Knijnikova, M. Kashlev, and S. M. Mirkin Effects of Friedreich's ataxia (GAA)n{middle dot}(TTC)n repeats on RNA synthesis and stability Nucleic Acids Res., February 28, 2007; 35(4): 1075 - 1084. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Burnett, C. Melander, J. W. Puckett, L. S. Son, R. D. Wells, P. B. Dervan, and J. M. Gottesfeld DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA{middle dot}TTC repeats in Friedreich's ataxia PNAS, August 1, 2006; 103(31): 11497 - 11502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Wells, R. Dere, M. L. Hebert, M. Napierala, and L. S. Son Advances in mechanisms of genetic instability related to hereditary neurological diseases Nucleic Acids Res., July 8, 2005; 33(12): 3785 - 3798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. I. Hashem, M. J. Pytlos, E. A. Klysik, K. Tsuji, M. Khajav, T. Ashizawa, and R. R. Sinden Chemotherapeutic deletion of CTG repeats in lymphoblast cells from DM1 patients Nucleic Acids Res., December 1, 2004; 32(21): 6334 - 6346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Pollard, R. Sharma, M. Gomez, S. Shah, M. B. Delatycki, L. Pianese, A. Monticelli, B. J.B. Keats, and S. I. Bidichandani Replication-mediated instability of the GAA triplet repeat mutation in Friedreich ataxia Nucleic Acids Res., November 8, 2004; 32(19): 5962 - 5971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Everett and N. W. Wood Trinucleotide repeats and neurodegenerative disease Brain, November 1, 2004; 127(11): 2385 - 2405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Krasilnikova and S. M. Mirkin Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo Mol. Cell. Biol., March 15, 2004; 24(6): 2286 - 2295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. N. Potaman, E. A. Oussatcheva, Y. L. Lyubchenko, L. S. Shlyakhtenko, S. I. Bidichandani, T. Ashizawa, and R. R. Sinden Length-dependent structure formation in Friedreich ataxia (GAA)n{middle dot}(TTC)n repeats at neutral pH Nucleic Acids Res., February 20, 2004; 32(3): 1224 - 1231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Vetcher and R. D. Wells Sticky DNA Formation in Vivo Alters the Plasmid Dimer/Monomer Ratio J. Biol. Chem., February 20, 2004; 279(8): 6434 - 6443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Napierala, R. Dere, A. Vetcher, and R. D. Wells Structure-dependent Recombination Hot Spot Activity of GAA{middle dot}TTC Sequences from Intron 1 of the Friedreich's Ataxia Gene J. Biol. Chem., February 20, 2004; 279(8): 6444 - 6454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Karthikeyan, J. H. Santos, M. A. Graziewicz, W. C. Copeland, G. Isaya, B. V. Houten, and M. A. Resnick Reduction in frataxin causes progressive accumulation of mitochondrial damage Hum. Mol. Genet., December 15, 2003; 12(24): 3331 - 3342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Weisman-Shomer, E. Cohen, I. Hershco, S. Khateb, O. Wolfovitz-Barchad, L. H. Hurley, and M. Fry The cationic porphyrin TMPyP4 destabilizes the tetraplex form of the fragile X syndrome expanded sequence d(CGG)n Nucleic Acids Res., July 15, 2003; 31(14): 3963 - 3970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Sharma, S. Bhatti, M. Gomez, R. M. Clark, C. Murray, T. Ashizawa, and S. I. Bidichandani The GAA triplet-repeat sequence in Friedreich ataxia shows a high level of somatic instability in vivo, with a significant predilection for large contractions Hum. Mol. Genet., September 1, 2002; 11(18): 2175 - 2187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Karthikeyan, L. K. Lewis, and M. A. Resnick The mitochondrial protein frataxin prevents nuclear damage Hum. Mol. Genet., May 16, 2002; 11(11): 1351 - 1362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Grabczyk and K. Usdin Alleviating transcript insufficiency caused by Friedreich's ataxia triplet repeats Nucleic Acids Res., December 15, 2000; 28(24): 4930 - 4937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sakamoto, J. E. Larson, R. R. Iyer, L. Montermini, M. Pandolfo, and R. D. Wells GGA{middle dot}TCC-interrupted Triplets in Long GAA{middle dot}TTC Repeats Inhibit the Formation of Triplex and Sticky DNA Structures, Alleviate Transcription Inhibition, and Reduce Genetic Instabilities J. Biol. Chem., July 13, 2001; 276(29): 27178 - 27187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sakamoto, K. Ohshima, L. Montermini, M. Pandolfo, and R. D. Wells Sticky DNA, a Self-associated Complex Formed at Long GAA{middle dot}TTC Repeats in Intron 1 of the Frataxin Gene, Inhibits Transcription J. Biol. Chem., July 13, 2001; 276(29): 27171 - 27177. [Abstract] [Full Text] [PDF]
|
|