Mosaic divergent repeat interruptions of motif length and sequence, mDRILS, of XDP-linked repeats affect formation of DNA/RNA triplexes & quadruplexes
6 affiliations
- 1Department of Chemical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Iran
- 2Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
- 3Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
- 4Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- 5Department of Molecular and Medical Genetics, University of Toronto, Canada
- 6The Hospital for Sick Children, Toronto, Canada
Abstract
An inserted SINE-VNTR-Alu(AGAGGG)n repeat into the TAF1 gene is the cause of X-linked dystonia-parkinsonism. Mosaic divergent repeat interruptions affecting both motif length and sequence (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)2AGGG(AGAGGG)-3’; and 5’-(AGAGGG)2AGG(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)2CCCT(CCCTCT)-3’, and 5’-(CCCTCT)2CCT(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.
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BibTeX
@article{soltani2026mosaic,
title = {{Mosaic divergent repeat interruptions of motif length and sequence, mDRILS, of XDP-linked repeats affect formation of DNA/RNA triplexes & quadruplexes}},
author = {Niousha Sharifi Soltani and Bita Zamiri and Amirreza Shafieeha and Ali Akbar Moosavi-Movahedi and Joshua Laß and Christine Klein and Ana Westenberger and Joanne Trinh and Sebastian Hönes and Christopher E. Pearson},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0360550},
url = {https://doi.org/10.1371/journal.pone.0360550},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mosaic divergent repeat interruptions of motif length and sequence, mDRILS, of XDP-linked repeats affect formation of DNA/RNA triplexes & quadruplexes
AU - Niousha Sharifi Soltani
AU - Bita Zamiri
AU - Amirreza Shafieeha
AU - Ali Akbar Moosavi-Movahedi
AU - Joshua Laß
AU - Christine Klein
AU - Ana Westenberger
AU - Joanne Trinh
AU - Sebastian Hönes
AU - Christopher E. Pearson
PY - 2026
DA - 2026/10/27
JO - PLOS One
DO - 10.1371/journal.pone.0360550
UR - https://doi.org/10.1371/journal.pone.0360550
AB - An inserted SINE-VNTR-Alu(AGAGGG)n repeat into the TAF1 gene is the cause of X-linked dystonia-parkinsonism. Mosaic divergent repeat interruptions affecting both motif length and sequence (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)2AGGG(AGAGGG)-3’; and 5’-(AGAGGG)2AGG(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)2CCCT(CCCTCT)-3’, and 5’-(CCCTCT)2CCT(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.
SN - 1932-6203
ER -