Mosaic divergent repeat interruptions of motif length and sequence, mDRILS, of XDP-linked repeats affect formation of DNA/RNA triplexes & quadruplexes

An inserted SINE-VNTR-Alu(AGAGGG)n repeat into the TAF1 gene is the cause of X-linked dystonia-parkinsonism. M osaic d ivergent r epeat i nterruptions affecting both motif l ength and s equence (mDRILS) of the canonical repeat (AGAGGG)n arise and can diminish repeat instability and delay disease age of onset. The repeat itself may affect gain-of-function disease pathways. Consequently, XDP etiology may involve unusual structures formed by the repeats. To study the effects of mDRILS on the formation of unusual structures of the XDP TAF1 -SVA repeat, we designed a series of G-rich DNA and RNA oligonucleotides having the pure canonical repeat 5’-(AGAGGG)4−3’, or either of the most common mDRILS 5’-(AGAGGG)2 AGGG (AGAGGG)-3’; and 5’-(AGAGGG)2 AGG (AGAGGG)-3’. Circular dichroism, thermal melting, binding of the G-quadruplex ligand TMPyP4, shows the first canonical and AGGG -interrupted sequence assume K ⁺ -sensitive stable G-quadruplexes, whereas GA duplexes are the prominent structure in the AGG -interrupted form. The complementary C-rich strands, 5’-(CCCTCT)4−3’, and 5’-(CCCTCT)2 CCCT (CCCTCT)-3’, and 5’-(CCCTCT)2 CCT (CCCTCT)-3’, assumed i -motif-compatible structure. Mixtures of the G- and C-rich complementary sequences, at 1:2 ratios, showed triplex-forming propensity for the canonical and AGGG-interrupted, but not the AGG-interrupted forms. The ability of mDRILS to elicit modifications of the disease-causing XDP TAF1 -SVA repeat to enable or disable the formation of specific structures, such as quadruplex and triplex structures, may explain in part how mDRILS mediate their disease-modifying effects.