1 research outputs found
Structure and Dynamics of RNA Repeat Expansions That Cause Huntington’s Disease and Myotonic Dystrophy Type 1
RNA repeat expansions cause a host
of incurable, genetically defined
diseases. The most common class of RNA repeats consists of trinucleotide
repeats. These long, repeating transcripts fold into hairpins containing
1 Ă— 1 internal loops that can mediate disease via a variety of
mechanism(s) in which RNA is the central player. Two of these disorders
are Huntington’s disease and myotonic dystrophy type 1, which
are caused by rÂ(CAG) and rÂ(CUG) repeats, respectively. We report the
structures of two RNA constructs containing three copies of a rÂ(CAG)
[rÂ(3Ă—CAG)] or rÂ(CUG) [rÂ(3Ă—CUG)] motif that were modeled
with nuclear magnetic resonance spectroscopy and simulated annealing
with restrained molecular dynamics. The 1 Ă— 1 internal loops
of rÂ(3Ă—CAG) are stabilized by one-hydrogen bond (<i>cis</i> Watson–Crick/Watson–Crick) AA pairs, while those of
rÂ(3Ă—CUG) prefer one- or two-hydrogen bond (<i>cis</i> Watson–Crick/Watson–Crick) UU pairs. Assigned chemical
shifts for the residues depended on the identity of neighbors or next
nearest neighbors. Additional insights into the dynamics of these
RNA constructs were gained by molecular dynamics simulations and a
discrete path sampling method. Results indicate that the global structures
of the RNA are A-form and that the loop regions are dynamic. The results
will be useful for understanding the dynamic trajectory of these RNA
repeats but also may aid in the development of therapeutics