Unexplored Territory “non-B form DNA/RNA”

Investigating the biological significance of the non-B form DNA/RNA structure in brain functions.

The double helix, twisted-ladder structure of DNA was discovered by Dr. James Watson, and Dr. Francis Crick in 1953. The structure of the double helix DNA is called “B-form DNA”. Actually, besides the right-handed double helix structure, a structure called “non-B form DNA” such as left-handed DNA, triple-stranded DNA, quadruple strand DNA, etc. has been discovered. Depend on the sequence and solvent environments, it can take structures other than B-form DNA structure. We focus on “G-quadruplex” which is one of non-B form DNA and RNA structure. The G-quadruplex is one of special high-order structures formed by single-stranded DNA or RNA in a guanine rich sequence region (Fig. 1).

1. Elucidation of the pathology of neurological diseases involving “non-B form DNA/RNA”.
2. Elucidation of the functional roles of RNA G-quadruplex in brain.

１．Elucidation of the pathology of neurological diseases involving “non-B form DNA/RNA”.

We are elucidating intracellular mechanisms and research on drug discovery using disease model mice showing cognitive function deficits. For example, X-linked α-thalassemia intellectual disability syndrome (ATR-X syndrome) and fragile X-associated tremor/ataxia syndrome (FXTAS) are hereditary neurological disorders involving abnormality of G-quadruplexes.

Also, in repeat expansion diseases such as FXTAS, Repeat-Associated Non-AUG (RAN) translation occurs, resulting production of polypeptide proteins is a cause of neurodegeneration. RAN translation is a molecular mechanism common to many repeat expansion diseases and it is considered to be a target for therapy. We are pursuing the mechanism by which “non-B type DNA / RNA” including G-quadruplex is triggered RAN translation (Fig. 2).

２．Elucidation of the functional roles of RNA G-quadruplex in brain.

The RNA G-quadruplex exists as a complex with the binding proteins in cytoplasm. We have analyzed immunoprecipitates from mouse brain tissue with a G-quadruplex structure recognition antibody using next-generation sequencer and LC-MS/MS shotgun proteomics, and identified constituents of the complexes. Currently, the physiological significance of these complexes in the mouse brain is examined (Fig. 3).