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

Students of Indian Institute of Technology, Hyderabad Yogeeshwar Ajjugal and Narendar Kolimi won the award for research work of 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. They carried their project work under the guidance of Dr Thenmalarchelvi Rathinavelan.

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 is to undergo abnormal expansion (viz. increase in repeat length) which leads to many incurable genetic disorders that are mainly neurodegenerative.

For instance, CGG repeat overexpansion in the 5’ untranslated region (UTR) of fragile mental retardation (fmr1) gene from unusual nucleic acid conformations and it 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 favour quadruplex 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 an 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.

The Hon’ble Vice President of India, Shri M. Venkaiah Naidu awarded the Gandhian Young Technological Innovation (GYTI) Award to Yogeeshwar Ajjugal and Narendar Kolimi Indian Institute of Technology, Hyderabad at the GYTI 2019 Awards function held at Vigyan Bhawan, New Delhi on July 06, 2019.

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