Abstract

Expansion of the GAA/TTC triplet repeats inside the first intron of the frataxin gene causes an autosomal disease named Friedeic's Ataxia. In normal phenotypes, 7-30 triplet repeats of GAA/TTC are present, whereas in disease phenotypes more than 200 copies appear and the mRNA of the frataxin gene is totally absent. It is our hypothesis that the formation of an unusual DNA structure by the GAA/TTC repeat causes its expansion and that this unusual structure is stabilized by higher repeat lengths. This also suggests that the formation of these same unusual structures during transcription causes the suppression of the mRNA synthesis. In this project, we have chosen a GAA/TTC sequence that forms a triple helix structure. In this triplex structure, the TTC strand folds back around the GAA strand and one side of the GAA strand interacts with the TTC strand via Watson-Crick base-pairing, whereas the other side of the GAA strand uses Hoogsteen base-pairing. We have started to measure 2D NMR experiments to determine the high resolution structure of this triplex. We plan to identify the nature of the TTC folding and the conformation of the three individual strands in the triplex. These studies will help us visualize how such a triplex structure can be formed during replication and transcription.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
2P41RR000995-24
Application #
6118665
Study Section
Project Start
1999-05-15
Project End
2000-04-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
24
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Massachusetts Institute of Technology
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139

  Publications

Marintchev, Assen; Edmonds, Katherine A; Marintcheva, Boriana et al. (2009) Topology and regulation of the human eIF4A/4G/4H helicase complex in translation initiation. Cell 136:447-60
Frueh, Dominique P; Arthanari, Haribabu; Koglin, Alexander et al. (2009) A double TROSY hNCAnH experiment for efficient assignment of large and challenging proteins. J Am Chem Soc 131:12880-1
Frueh, Dominique P; Leed, Alison; Arthanari, Haribabu et al. (2009) Time-shared HSQC-NOESY for accurate distance constraints measured at high-field in (15)N-(13)C-ILV methyl labeled proteins. J Biomol NMR 45:311-8
Lentz, Margaret R; Westmoreland, Susan V; Lee, Vallent et al. (2008) Metabolic markers of neuronal injury correlate with SIV CNS disease severity and inoculum in the macaque model of neuroAIDS. Magn Reson Med 59:475-84
Hyberts, Sven G; Heffron, Gregory J; Tarragona, Nestor G et al. (2007) Ultrahigh-resolution (1)H-(13)C HSQC spectra of metabolite mixtures using nonlinear sampling and forward maximum entropy reconstruction. J Am Chem Soc 129:5108-16
Chen, Jingyang; Dupradeau, Francois-Yves; Case, David A et al. (2007) Nuclear magnetic resonance structural studies and molecular modeling of duplex DNA containing normal and 4'-oxidized abasic sites. Biochemistry 46:3096-107
Lentz, Margaret R; Kim, John P; Westmoreland, Susan V et al. (2005) Quantitative neuropathologic correlates of changes in ratio of N-acetylaspartate to creatine in macaque brain. Radiology 235:461-8
Kim, John P; Lentz, Margaret R; Westmoreland, Susan V et al. (2005) Relationships between astrogliosis and 1H MR spectroscopic measures of brain choline/creatine and myo-inositol/creatine in a primate model. AJNR Am J Neuroradiol 26:752-9
Peled, S; Cory, D G; Raymond, S A et al. (1999) Water diffusion, T(2), and compartmentation in frog sciatic nerve. Magn Reson Med 42:911-8
Mo, H; Dai, Y; Pochapsky, S S et al. (1999) 1H, 13C and 15N NMR assignments for a carbon monoxide generating metalloenzyme from Klebsiella pneumoniae. J Biomol NMR 14:287-8

Showing the most recent 10 out of 12 publications