Twisting Right to Left: A…A Mismatch in a CAG Trinucleotide Repeat Overexpansion Provokes Left-Handed Z-DNA Conformation

Rathinavelan, Thenmalarchelvi (2015) Twisting Right to Left: A…A Mismatch in a CAG Trinucleotide Repeat Overexpansion Provokes Left-Handed Z-DNA Conformation. In: International congress on DNA structure in Health and Disease, 12-13 April 2015, New Delhi, India.

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Abstract

Conformational polymorphism of DNA is a major causative factor behind several incurable trinucleotide repeat expansion disorders that arise from overexpansion of trinucleotide repeats located in coding/non-coding regions of specific genes. Hairpin DNA structures that are formed due to overexpansion of CAG repeat lead to Huntington’s disorder and spinocerebellar ataxias. Nonetheless, DNA hairpin stem structure that generally embraces B-form with canonical base pairs is poorly understood in the context of periodic noncanonical A…A mismatch as found in CAG repeat overexpansion. Molecular dynamics simulations on DNA hairpin stems containing A…A mismatches in a CAG repeat overexpansion show that A…A dictates local Z-form irrespective of starting glycosyl conformation, in sharp contrast to canonical DNA duplex. Transition from B-to-Z is due to the mechanistic effect that originates from its pronounced nonisostericity with flanking canonical base pairs facilitated by base extrusion, backbone and/or base flipping. Based on these structural insights we envisage that such an unusual DNA structure of the CAG hairpin stem may have a role in disease pathogenesis. As this is the first study that delineates the influence of a single A…A mismatch in reversing DNA helicity, it would further have an impact on understanding DNA mismatch repair.

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IITH Creators:
IITH CreatorsORCiD
Rathinavelan, Thenmalarchelvihttp://orcid.org/0000-0002-1142-0583
Item Type: Conference or Workshop Item (Paper)
Subjects: Others > Biotechnology
Divisions: Department of Biotechnology
Depositing User: Library Staff
Date Deposited: 21 Aug 2019 09:26
Last Modified: 21 Aug 2019 09:26
URI: http://raiith.iith.ac.in/id/eprint/5985
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