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Large-Scale Contractions of Friedreich's Ataxia GAA Repeats in Yeast Occur During DNA Replication Due to Their Triplex-Forming

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Large-Scale Contractions of Friedreich's Ataxia GAA Repeats in Yeast Occur During DNA Replication Due to Their Triplex-Forming Large-scale contractions of Friedreich’s ataxia GAA repeats in yeast occur during DNA replication due to their triplex-forming ability Alexandra N. Khristicha, Jillian F. Armeniaa, Robert M. Materaa, Anna A. Kolchinskia, and Sergei M. Mirkina,1 aDepartment of Biology, Tufts University, Medford, MA 02155 Edited by Sue Jinks-Robertson, Duke University School of Medicine, Durham, NC, and approved December 12, 2019 (received for review August 2, 2019) Friedreich’s ataxia (FRDA) is a human hereditary disease caused by contain either one purine and two pyrimidine strands (YR*Y the presence of expanded (GAA)n repeats in the first intron of the triplex) or one pyrimidine and two purine strands (YR*R triplex) FXN gene [V. Campuzano et al., Science 271, 1423–1427 (1996)]. In (27). GAA repeats form both types of triplexes in supercoiled somatic tissues of FRDA patients, (GAA)n repeat tracts are highly DNA in vitro, but there are conflicting reports on which of them unstable, with contractions more common than expansions is more stable under physiological conditions (26, 28–32). [R. Sharma et al., Hum. Mol. Genet. 11, 2175–2187 (2002)]. Here we Understanding the mechanism of GAA repeat contractions is describe an experimental system to characterize GAA repeat contrac- very important, as facilitating contractions might help reverse the tions in yeast and to conduct a genetic analysis of this process. We progression of this currently incurable disease. However, the found that large-scale contraction is a one-step process, resulting in a mechanisms of GAA repeat contractions are not yet understood. median loss of ∼60 triplet repeats. Our genetic analysis revealed that Earlier studies in bacteria suggested that contractions of GAA contractions occur during DNA replication, rather than by various DNA repeats were linked to RecA-mediated replication fork restart repair pathways. Repeats contract in the course of lagging-strand syn- (33) or double-strand break (DSB) repair via the single-strand thesis: The processivity subunit of DNA polymerase δ, Pol32, and the annealing (SSA) pathway (34). In mammalian systems, contrac- catalytic domain of Rev1, a translesion polymerase, act together in the tions were counteracted by mismatch repair (MMR) (35) and same pathway to counteract contractions. Accumulation of single- promoted by base excision repair (BER) (36). stranded DNA (ssDNA) in the lagging-strand template greatly increases To distinguish between various possible mechanisms that could the probability that (GAA)n repeats contract, which in turn promotes lead to large-scale GAA repeat contractions, we developed an repeat instability in rfa1, rad27,anddna2 mutants. Finally, by compar- experimental system to conduct quantitative genetic analysis of ing contraction rates for homopurine-homopyrimidine repeats differ- this process in yeast, Saccharomyces cerevisiae. We found that re- ing in their mirror symmetry, we found that contractions depend on peat contractions predominantly occur during DNA replication, a repeat’s triplex-forming ability. We propose that accumulation of likely in the course of lagging-strand synthesis. Contraction rates ssDNA in the lagging-strand template fosters the formation of a triplex of various homopurine-homopyrimidine repeats appear to relate between the nascent and fold-back template strands of the repeat. to their ability to form triplexes. We conclude that contractions Occasional jumps of DNA polymerase through this triplex hurdle, re- result from a triplex bypass during lagging-strand synthesis. sult in repeat contractions in the nascent lagging strand. Results repeat expansion diseases | repeat contractions | Friedreich’s ataxia | An Experimental System to Study Large-Scale GAA Repeat Contractions DNA triplex | DNA replication in Yeast. To measure the rate of large-scale contractions of GAA repeats in yeast, we used a genetic cassette containing the (GAA)124 riedreich’s ataxia (FRDA) is the most common hereditary Fataxia in humans. This autosomal recessive genetic disease is Significance caused by the presence of an expanded GAA repeat tract in the first intron of the FXN gene, which encodes for frataxin, a pro- Expansions of GAA repeats cause a severe hereditary neurode- tein required for proper mitochondrial function (1). Healthy generative disease, Friedreich’s ataxia. In this study, we charac- people usually have 8 to 34 GAA repeats, carriers have 35 to 70 terized the mechanisms of GAA repeat contractions in a yeast repeats, and affected individuals have more than 70 repeats, experimental system. These mechanisms might, in the long run, commonly hundreds of repeats (2–4). aid development of a therapy for this currently incurable dis- The number of expanded GAA repeats negatively correlates ease. We show that GAA repeats contract during DNA replica- with disease onset and positively correlates with disease severity tion, which can explain the high level of somatic instability of (4–6). This is because expanded GAA repeats impede expression this repeat in patient tissues. We also provided evidence that a of the FXN gene at the transcription level (1, 7–9), which ulti- triple-stranded DNA structure is at the heart of GAA repeat in- mately leads to mitochondrial dysfunction (10, 11). Expanded stability. This discovery highlights the role of triplex DNA in GAA repeats are also known to stall replication fork progression genome instability and human disease. (7, 12–14) and induce mutagenesis in the surrounding DNA both in – Author contributions: A.N.K. and S.M.M. designed research; A.N.K., J.F.A., R.M.M., and patient cells (15) and model organisms (16 18). In a yeast experi- A.A.K. performed research; A.N.K. and S.M.M. analyzed data; and A.N.K. and S.M.M. mental system, they also promote chromosomal fragility (19), mi- wrote the paper. totic cross-overs (20), and complex genomic rearrangements (21). The authors declare no competing interest. Not surprisingly, therefore, long (GAA)n runs are very un- This article is a PNAS Direct Submission. stable in length and are prone to both expansions and contrac- This open access article is distributed under Creative Commons Attribution-NonCommercial- tions. Long tracts of GAA repeats are also particularly unstable NoDerivatives License 4.0 (CC BY-NC-ND). in somatic tissues (22), with contractions more common than 1To whom correspondence may be addressed. Email: [email protected]. expansions (23, 24). It was hypothesized that the instability of This article contains supporting information online at https://www.pnas.org/lookup/suppl/ GAA repeats is due to their ability to form an intramolecular doi:10.1073/pnas.1913416117/-/DCSupplemental. DNA triplex, also known as H-DNA (25, 26). This triplex may First published January 7, 2020. 1628–1637 | PNAS | January 21, 2020 | vol. 117 | no. 3 www.pnas.org/cgi/doi/10.1073/pnas.1913416117 Downloaded by guest on September 25, 2021 repeat within an artificial intron of the URA3 gene located under occur independently from small-scale repeat contractions, one the control of the inducible Gal promoter (37). In this setting, the would expect to see a disproportionally large number of colonies (GAA)124 repeat tract constitutes a template for lagging-strand with short repeats that did not originate from the exponential synthesis and is in the sense strand for URA3 transcription, mim- distribution. icking the position of the (GAA)n run in the human FXN gene (1). Experimentally, we observed a large number of small-scale repeat Due to yeast’s inability to splice out long introns, cells containing contractions (one to three repeats) clustering around the initial – this cassette are Ura . Contractions of more than 20 repeats enable repeat tract size in colonies grown without selection. However, + splicing, thus making cells Ura when galactose is present in the there was a distinct additional cluster of repeat lengths around media (Fig. 1A). 70 GAA repeats, as well as 7 colonies carrying large repeat ex- To confirm that we selected for repeat contractions, we am- pansions (Fig. 1 D and E). The lower half of the distribution plified the repeat tract from randomly selected colonies that had corresponding to repeat contractions failed to fit an exponential – − grown on the selective Ura media for 4 d (Fig. 1C). Of 183 an- model (Kolmogorov–Smirnov test, P = 2.3·10 13), unless we only alyzed colonies, 91% revealed a repeat tract that was significantly included small-scale contractions (Kolmogorov–Smirnov test, + shorter than the original. Thus, the Ura rate was practically in- P = 0.067) categorized by k-means clustering analysis (Fig. 1 D distinguishable from the bona fide repeat contraction rate (Fig. and E). We conclude that large-scale repeat contractions occur 1B), which also was true for the various mutants tested (SI Ap- independently from small-scale contractions. + pendix, Fig. S2 and Table S1). Therefore, we used the Ura rate as We then compared the size distribution of large-scale repeat a proxy for the repeat contraction rate throughout this study. contractions from colonies grown with and without selection. The distribution of contracted repeat lengths revealed that the The median size of contracted repeats was only slightly smaller median size of the repeat tract in a colony grown on the selective under selective conditions than without selection (60 vs. 70 repeats) media was 60 GAA repeats (Fig. 1D); that is, roughly half of the (Fig. 1B). Thus, selective pressure did not significantly affect the repeat tract was lost. This loss could have resulted from a single scale of repeat contractions in our system. Overall, these data show large-scale contraction event or from consecutive small-scale re- that long GAA repeats are prone to large-scale contractions in yeast peat contractions. To distinguish between these possibilities, we that seem to occur in one step. measured the distribution of repeat sizes in yeast colonies that were grown without any selective pressure. If large-scale con- Impaired Lagging-Strand Replication Facilitates GAA Repeat Contractions.
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