@article{kandola_venkatesan_zhang_lerbakken_von schulze_blanck_wu_unruh_berry_lange_et al._2023, title={Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal}, volume={12}, ISSN={["2050-084X"]}, DOI={10.7554/eLife.86939}, abstractNote={A long-standing goal of amyloid research has been to characterize the structural basis of the rate-determining nucleating event. However, the ephemeral nature of nucleation has made this goal unachievable with existing biochemistry, structural biology, and computational approaches. Here, we addressed that limitation for polyglutamine (polyQ), a polypeptide sequence that causes Huntington’s and other amyloid-associated neurodegenerative diseases when its length exceeds a characteristic threshold. To identify essential features of the polyQ amyloid nucleus, we used a direct intracellular reporter of self-association to quantify frequencies of amyloid appearance as a function of concentration, conformational templates, and rational polyQ sequence permutations. We found that nucleation of pathologically expanded polyQ involves segments of three glutamine (Q) residues at every other position. We demonstrate using molecular simulations that this pattern encodes a four-stranded steric zipper with interdigitated Q side chains. Once formed, the zipper poisoned its own growth by engaging naive polypeptides on orthogonal faces, in a fashion characteristic of polymer crystals with intramolecular nuclei. We further show that self-poisoning can be exploited to block amyloid formation, by genetically oligomerizing polyQ prior to nucleation. By uncovering the physical nature of the rate-limiting event for polyQ aggregation in cells, our findings elucidate the molecular etiology of polyQ diseases.}, journal={ELIFE}, author={Kandola, Tej and Venkatesan, Shriram and Zhang, Jiahui and Lerbakken, Brooklyn T. and Von Schulze, Alex and Blanck, Jillian F. and Wu, Jianzheng and Unruh, Jay R. and Berry, Paula and Lange, Jeffrey J. and et al.}, year={2023}, month={Nov} }
 @article{fakharzadeh_zhang_roland_sagui_2022, title={Novel eGZ-motif formed by regularly extruded guanine bases in a left-handed Z-DNA helix as a major motif behind CGG trinucleotide repeats}, ISSN={["1362-4962"]}, DOI={10.1093/nar/gkac339}, abstractNote={Abstract}, journal={NUCLEIC ACIDS RESEARCH}, author={Fakharzadeh, Ashkan and Zhang, Jiahui and Roland, Christopher and Sagui, Celeste}, year={2022}, month={May} }
 @article{zhang_fakharzadeh_roland_sagui_2022, title={RNA as a Major-Groove Ligand: RNA-RNA and RNA-DNA Triplexes Formed by GAA and UUC or TTC Sequences}, volume={7}, ISSN={["2470-1343"]}, DOI={10.1021/acsomega.2c04358}, abstractNote={Friedreich’s ataxia is associated with noncanonical nucleic acid structures that emerge when GAA:TTC repeats in the first intron of the FXN gene expand beyond a critical number of repeats. Specifically, the noncanonical repeats are associated with both triplexes and R-loops. Here, we present an in silico investigation of all possible triplexes that form by attaching a third RNA strand to an RNA:RNA or DNA:DNA duplex, complementing previous DNA-based triplex studies. For both new triplexes results are similar. For a pyridimine UUC+ third strand, the parallel orientation is stable while its antiparallel counterpart is unstable. For a neutral GAA third strand, the parallel conformation is stable. A protonated GA+A third strand is stable in both parallel and antiparallel orientations. We have also investigated Na+ and Mg2+ ion distributions around the triplexes. The presence of Mg2+ ions helps stabilize neutral, antiparallel GAA triplexes. These results (along with previous DNA-based studies) allow for the emergence of a complete picture of the stability and structural characteristics of triplexes based on the GAA and TTC/UUC sequences, thereby contributing to the field of trinucleotide repeats and the associated unusual structures that trigger expansion.}, number={43}, journal={ACS OMEGA}, author={Zhang, Jiahui and Fakharzadeh, Ashkan and Roland, Christopher and Sagui, Celeste}, year={2022}, month={Nov}, pages={38728–38743} }
 @article{zhang_fakharzadeh_pan_roland_sagui_2021, title={Construction of DNA/RNA Triplex Helices Based on GAA/TTC Trinucleotide Repeats}, volume={11}, ISSN={["2331-8325"]}, DOI={10.21769/BioProtoc.4155}, abstractNote={Atypical DNA and RNA secondary structures play a crucial role in simple sequence repeat (SSR) diseases, which are associated with a class of neurological and neuromuscular disorders known as "anticipation diseases," where the age of disease onset decreases and the severity of the disease is increased as the intergenerational expansion of the SSR increases. While the mechanisms underlying these diseases are complex and remain elusive, there is a consensus that stable, non-B-DNA atypical secondary structures play an important - if not causative - role. These structures include single-stranded DNA loops and hairpins, G-quartets, Z-DNA, triplex nucleic acid structures, and others. While all of these structures are of interest, structures based on nucleic acid triplexes have recently garnered increased attention as they have been implicated in gene regulation, gene repair, and gene engineering. Our work here focuses on the construction of DNA triplexes and RNA/DNA hybrids formed from GAA/TTC trinucleotide repeats, which underlie Friedreich's ataxia. While there is some software, such as the Discovery Studio Visualizer, that can aid in the initial construction of DNA triple helices, the only option for the triple helix is constrained to be that of an antiparallel pyrimidine for the third strand. In this protocol, we illustrate how to build up more generalized DNA triplexes and DNA/RNA mixed hybrids. We make use of both the Discovery Studio Visualizer and the AMBER simulation package to construct the initial triplexes. Using the steps outlined here, one can - in principle - build up any triple nucleic acid helix with a desired sequence for large-scale molecular dynamics simulation studies.}, number={18}, journal={BIO-PROTOCOL}, author={Zhang, Jiahui and Fakharzadeh, Ashkan and Pan, Feng and Roland, Christopher and Sagui, Celeste}, year={2021}, month={Sep} }
 @article{zhang_fakharzadeh_pan_roland_sagui_2020, title={Atypical structures of GAA/TTC trinucleotide repeats underlying Friedreich's ataxia: DNA triplexes and RNA/DNA hybrids}, volume={48}, ISSN={["1362-4962"]}, DOI={10.1093/nar/gkaa665}, abstractNote={Abstract}, number={17}, journal={NUCLEIC ACIDS RESEARCH}, author={Zhang, Jiahui and Fakharzadeh, Ashkan and Pan, Feng and Roland, Christopher and Sagui, Celeste}, year={2020}, month={Sep}, pages={9899–9917} }