A Frustrated Trio

NEWS & VIEWS RESEARCH skin cells in which melanoma arises) are 4. Hodis, E. et al. Cell 150, 251–263 (2012). 8. Jané-Valbuena, J. et al. Cancer Res. 70, 2075–2084 especially sensitive to changes in TERT expres- 5. Krauthammer, M. et al. Nature Genet. 44, (2010). 1006–1014 (2012). 9. Capper, R. et al. Genes Dev. 21, 2495–2508 (2007). sion, because in Horn and colleagues’ study all 6. Harrington, L. Mutat. Res. 730, 37–42 (2012). 10. Xu, L. & Blackburn, E. H. Mol. Cell 28, 315–327 but one person carrying the T-to-G mutation 7. Ding, Z. et al. Cell 148, 896–907 (2012). (2007). developed melanoma, and the unaffected car- rier had multiple naevi. This susceptibility could arise because ETS proteins are targets CONDENSED-MATTER PHYSICS of the MAPK cell-signalling pathway, which is frequently activated in melanoma and benign naevi. In support of this idea, Horn and colleagues found that the TERT-promoter A frustrated trio mutations were found in many of the melanomas that had activating BRAF mutations; Geometrical frustration results from an incompatibility between the spatial BRAF is an intermediate in the MAPK path- arrangement of a system’s constituents and the interactions between them. way, and perhaps increased BRAF signalling The effect has now been observed in a triangular triple quantum dot. leads to enhanced activation of ETS factors at the TERT promoter. Another, non-mutually exclusive possibility SABINE ANDERGASSEN interesting situation arises when the system’s is that tissue-specific expression of ETS lattice geometry inhibits the formation of an proteins causes some cell types to become rustration arises when competing ordered, low-temperature spin configuration. particularly vulnerable to the effects of TERT- interactions cannot be satisfied simul- The origin of this effect is remarkably simple, promoter mutations. Indeed, ETS transcrip- taneously. This compromise is central and can be illustrated by three spins interacting tion factors are expressed in melanomas8. Fto the behaviour of many complex systems, antiferromagnetically on a triangular lattice. Furthermore, the T-to-G germline mutation from neural networks to folding proteins and Once two of the spins on an elementary trian- identified by Horn et al. generates a bind- magnetic materials. Writing in Physical Review gle are anti-aligned, the third one is ‘frustrated’: ing site that may be more selective for Elk1 Letters, Seo et al.1 describe experiments on a it can no longer point in a direction opposite to and Elk4, a subgroup of ETS that is highly simple frustrated system that make a promising both of the other spins. This incompatibility of expressed in the ovary, and the authors report step towards our understanding of the mecha- antiferromagnetic interactions with the under- that two women with this TERT-promoter nisms governing the physics of frustration. lying lattice geometry is known as geometrical mutation also developed ovarian cancer. In condensed-matter physics, frustration frustration, and is particularly pronounced These studies reveal two conceptual is a feature of magnetic materials that have in low dimensions, in which the effects of advances. First, they represent an unusual type competing interactions between localized interactions prevail. of driver mutation in cancer — one that need magnetic moments (spins). In a ferromagnet, The simple, and at the same time, funda- not modify the gene product itself, but instead the spins align with one another and result in mental model of geometrical frustration in a creates a binding site for transcriptional activa- a macroscopic magnetic moment. By contrast, triangle exhibits six competing lowest-energy tors that leads to an increase in normal gene in an antiferromagnet, neighbouring spins spin configurations with the same energy expression. Second, they show that changes point in opposite directions and the system (degenerate ground states). The resulting in TERT expression may be sufficient to exhibits no such macroscopic moment. An fluctuations between these states suppress cooperate with cancer-initiating oncogenes to drive cancers such as melanoma. A crucial next experiment will be to examine the func- tional consequences of the increase in TERT expression in patients with TERT-promoter mutations, to see whether it confers a survival advantage through a decrease in the incidence Quantum dot of short or fused telomeres that often persist in dividing cancer cells9,10. Taken together, the findings suggest that cancer development can Gate electrodes ? be driven by relatively subtle changes in the expression level of a normal gene, indicating that trouble can lie upstream of genes as well as within them. ■ ?

E. Elizabeth Patton is at the MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK. Lea Harrington is at the Wellcome Trust Centre for Cell Biology, Edinburgh EH9 3JR, UK, and the Institute for Research in Immunology and Cancer, University of Montreal, Canada. e-mails: [email protected]; Figure 1 | Geometrical frustration in a triangle of three quantum dots. In a triangular triple quantum dot in which the dots’ electron spins (arrows) interact antiferromagnetically, if two of the quantum dots [email protected] are in the ‘up’ and ‘down’ spin states, respectively, owing to the triangular geometry of the system, the spin 1. Huang, F. W. et al. Science 339, 957–959 (2013). of the third quantum dot is frustrated as it can align opposite to only one of the other spins. As a result, 2. Horn, S. et al. Science 339, 959–961 (2013). there are six configurations (all possible combinations of spin-up and spin-down except for the two in 3. Pleasance, E. D. et al. Nature 463, 191–196 which all three spins align) with the same energy. By controlling the system with gate electrodes, Seo and (2010). colleagues1 observe this sixfold degeneracy.

21 MARCH 2013 | VOL 495 | NATURE | 321 © 2013 Macmillan Publishers Limited. All rights reserved RESEARCH NEWS & VIEWS conventional ordering and the system features further experimental as well as theoretical e-mail: [email protected] non-zero entropy even at zero temperature, studies, including analysis of the time evolu- 1. Seo, M. et al. Phys. Rev. Lett. 110, 046803 in contrast to the naive expectation from tion of frustrated quantum systems. Quan- (2013). the third law of thermodynamics. Quantum tum dots have been suggested as potential 2. Bramwell, S. T. & Gingras, M. J. P. Science 294, superposition of degenerate states leads to platforms for implementing spin or charge 1495–1501 (2001). the emergence of exotic many-body phenom- quantum bits10–14 for quantum computation 3. Ramirez, A. Nature 399, 527–528 (1999). 2–6 4. Balents, L. Nature 464, 199–208 (2010). ena , from spin ice and quantum spin liquids and information processing. Control of mag- 5. Pratt, F. et al. Nature 471, 612–616 (2011). to high-temperature superconductivity. netism on the atomic scale is also becoming 6. Bramwell, S. T. et al. Nature 461, 956–959 A key characteristic of frustrated systems is essential as data-storage devices are miniatur- (2009). 7. Bloch, I. Nature 453, 1016–1022 (2008). a large number of degenerate ground states. ized. In particular, switchable nanoscale anti- 8. Bloch, I., Dalibard, J. & Zwerger, W. Rev. Mod. Phys. This high degeneracy is very sensitive to per- ferromagnets are being discussed as candidate 80, 885–964 (2008). turbations: any slight asymmetry in the system building blocks for future memory, storage and 9. Bloch, I., Dalibard, J. & Nascimbène, S. Nature Phys. will reduce the number of degenerate ground ‘spintronic’ applications15. Understanding the 8, 267–276 (2012). 10. Loss, D. & DiVincenzo, D. P. Phys. Rev. A 57, states. This instability leads to rich physical underlying physics will be crucial for the devel- 120–126 (1998). behaviour. Understanding the fundamental opment of these technologies. The challenge 11. Petta, J. R. et al. Science 309, 2180–2184 mechanisms and principles underlying the is the scalability to large systems — to explore (2005). 12. Koppens, F. H. L. et al. Nature 442, 766–771 variety of quantum phenomena that arise from complex many-body phenomena, identify (2006). highly degenerate ground states is of concep- novel quantum phases and design interesting 13. Hanson, R., Kouwenhoven, L. P., Petta, J. R., tual importance in condensed-matter physics. quantum materials. ■ Tarucha, S. & Vandersypen, L. M. K. Rev. Mod. Phys. Both the development of numerical-simula- 79, 1217–1265 (2007). 14. Pioro-Ladrière, M. et al. Nature Phys. 4, 776–779 tion techniques and the increasing ability to Sabine Andergassen is in the Faculty of (2008). experimentally engineer systems in which Physics, University of Vienna, 1090 Vienna, 15. Loth, S., Baumann, S., Lutz, C. P., Eigler, D. M. & magnetic, charge or vibrational degrees of free- Austria. Heinrich, A. J. Science 335, 196–199 (2012). dom interact, have a central role in address- ing this problem. In particular, optical lattices (arrays of interfering laser beams) of cold MOLECULAR BIOLOGY atoms7–9 provide model systems for strongly interacting many-body systems. Quantum dots (artificial atoms) provide a promising platform for investigating non- Circles reshape equilibrium charge transport, and in particular how it is affected by geometrical frustration. Advanced techniques for fabricating nanoscale the RNA world devices allow detailed modelling and flexible tuning of parameters. In semiconductor quan- The versatility of RNA seems limitless. The latest surprise comes from tum dots, the potential in which the dots are circular RNAs, which are found to counteract the function of another class confined and the number of electrons, as well of regulatory RNA — the microRNAs. See Article p.333 & Letter p.384 as the interaction between them, are controlled by metallic ‘gate’ electrodes. In their study, Seo et al. report the first obser- KENNETH S. KOSIK thousands of circRNAs reside in the genome, vation of geometrical frustration in quantum consistent with previous reports3,4. dots. Because of the difficulties in building he protein-coding function of mes- Target suppression by miRNAs is highly highly symmetrical devices, this had not been senger RNAs can be suppressed by the nuanced. On the one hand, these sequences achievable previously. Their frustrated quan- binding of short microRNA sequences. can induce AGO-mediated endonucleolytic tum system consists of three quantum dots TBut how microRNA-induced suppression is mRNA cleavage triggered by complemen- arranged in a triangle (Fig. 1). Antiferromag- itself inhibited is poorly understood. In this tarity between the mRNA and the miRNA netic interactions between the dots’ electron issue, Memczak et al.1 (page 333) and Hansen at nucleotides 10 and 11. The destruction of spins lead to a frustrated ground state, which et al.2 (page 384) describe highly stable, circular the target, which follows, frees the miRNA to results from the competition of the six degen- RNAs that bind several copies of a microRNA bind to its next target in a catalytic manner. On erate, three-spin configurations out of eight to terminate suppression of mRNA targets*. the other hand, miRNAs can inhibit protein possible spin arrangements. Because control- The circular RNA (circRNA) reported, translation by binding more stably to a tar- ling electron spins in quantum dots is difficult, called CDR1as by Memczak et al. and ciRS-7 get mRNA in a stoichiometric manner. This the authors used an alternative way of study- by Hansen et al., contains roughly 70 evolu- makes the target a ‘reservoir’ that prevents the ing geometrical frustration: degenerate charge tionarily conserved binding sites for micro- miRNA from inhibiting other mRNA targets. states. The advantage of this approach is that RNA-7 (miR-7) and forms a complex with The latter mechanism is an indication of the these charge states (isospins) are defined by AGO proteins. The latter are part of the RNA- way in which competing endogenous RNAs the parity of the number of charge carriers induced silencing complex, which allows (ceRNAs) act. These are mRNAs that share in the dots and can be precisely controlled by miRNAs to recognize their target mRNAs. miRNA-response elements (MREs) with other metallic gate electrodes. The authors’ measure- When Memczak and colleagues expressed mRNAs and so compete for binding to those ments of charge transport revealed the six-fold human CDR1as/ciRS-7 in zebrafish embryos, miRNAs with which they also share MREs5. degeneracy of the isospin configurations in the its effects were the same as those seen when Like ceRNAs, circRNAs serve as miRNA maximum electrical conductance induced by miR-7 expression was reduced — impaired reservoirs. However, circRNAs have numerous the fluctuations between the states. midbrain development. Moreover, the authors’ binding sites for a specific miRNA and so are Seo and colleagues’ work sheds light on the bioinformatic predictions indicated that completely dedicated to their role of harbour- impact of frustration on charge transport and *This article and the papers under discussion1,2 were ing miRNAs. Binding of a miRNA to a ceRNA its characteristic signatures, and motivates published online on 27 February 2013. not only prevents that miRNA from binding to