Revelation Of G-quadruplex Formation As A Molecular Basis Of Fragile X Tremor/ataxia Syndrome (fxtas) Leads To A New Direction In The Drug Discovery
Project Description :

Trinucleotide repeats belong to the family of microsatellites (a tract of 1 to 6 repetitive nucleotides) that are commonly observed in eukaryotes and exhibit repeat length polymorphism. the inherent ability of trinucleotide repeats to undergo abnormal expansion (viz. increase in repeat length) leads to many incurable genetic disorders that are mainly neurodegenerative. for instance, cgg repeat overexpansion in the 5’ un-translated region (utr) of fragile mental retardation (fmr1) gene form unusual nucleic acid conformations and causes genetic instabilities. this results in fragile x syndrome (fxs) and fragile x tremor/ataxia syndrome (fxtas). we have shown here that the number of g...g/c...c mismatches dictate the secondary structural choice of the sense and antisense strands of fmr1 gene and the corresponding transcripts. circular dichroism (cd) spectra reveal that cgg sense strand and its transcript favourquadruplex structure due to the intolerance for periodic g...g mismatch in a hairpin/duplex. further, cd and molecular dynamics simulations show that more than four c...c mismatches cannot be accommodated in a rna duplex consisting of ccg repeat (antisense transcript), instead, i-motif structure is favored. in contrast, ccg can form hairpin/duplex structure at the dna (antisense strand) level irrespective of the number of c...c mismatches. such unusual structures may be responsible for the increased r-loop stability, bidirectional transcription, rna foci formation and repeat associated non-aug translation for monopolypeptide aggregates in fxtas, a mechanism similar to c9orf72 ggggcc repeat expansion that causes amyotrophic lateral sclerosis. the results presented here also suggest that g-quadruplex structure observed in fmr1 gene and its transcript can be a potential drug target.

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Project Details :
  • Date : Oct 21,2018
  • Innovator : yogeeshwar ajjugal
  • Team Members : Narendar Kolimi,Thenmalarchelvi Rathinavelan
  • Guide Name : Thenmalarchelvi Rathinavelan
  • University : Indian Institutes of Technology Hyderabad
  • Submission Year : 2019
  • Category : Bioengineering / Biotech
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