Several aspects of the proposal, which aims to expand open access, require serious discussion and, in some cases, a rethink.
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Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine
Deyu Li, Bogdan I. Fedeles, Vipender Singh, Chunte Sam Peng, Katherine J. Silvestre, Allison K. Simi, Jeffrey H. Simpson, Andrei Tokmakoff, and John M. Essigmann
Unlike conventional antiviral therapy, lethal mutagenesis is a therapeutic strategy that exploits the high mutation rates of certain viruses. It works by intentionally increasing the viral mutation rate, causing excessive error accumulation and viral population collapse. The mutagenic nucleoside analog 5-aza-5,6-dihydro-2′-deoxycytidine (KP1212) is specifically designed to use lethal mutagenesis against HIV. The mechanism of KP1212 mutagenesis was proposed to involve tautomerism—the repositioning of active protons on the nucleic acid base on a fast time scale. Using a multifaceted approach, we demonstrate that KP1212 exists in multiple tautomeric forms, and that the tautomeric distribution correlates with the mutagenic properties of KP1212. This work (pp. E3252–E3259) also provides a toolset for studying tautomerism in nucleic acids and developing the next-generation antiviral lethal mutagens.
CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB–MYC involvement
Antonio L. Amelio, Mohammad Fallahi, Franz X. Schaub, Min Zhang, Mariam B. Lawani, Adam S. Alperstein, Mark R. Southern, Brandon M. Young, Lizi Wu, Maria Zajac-Kaye, Frederic J. Kaye, John L. Cleveland, and Michael D. Conkright
The prevailing dogma since the identification of the t (11, 19) translocation gene product as a fusion of the cAMP response element binding protein (CREB)-regulated transcriptional coactivator 1 (CRTC1) and the NOTCH coactivator mastermind-like 2 (MAML2) in malignant salivary gland tumors has been that aberrant activation of CREB and/or NOTCH transcription programs drives oncogenesis. However, combined expression of the parental coactivator molecules CRTC1 and MAML2 is not sufficient to induce transformation, suggesting an added level of complexity. Here (pp. E3260–E3268) we describe gain-of-function interactions between the CRTC1/MAML2 (C1/M2) coactivator fusion and myelocytomatosis oncogene (MYC) oncoproteins that are necessary for C1/M2-driven transformation. Our findings suggest that targeting the C1/M2–MYC interface represents an attractive strategy for the development of effective and safe anticancer therapeutics in tumors harboring the t (11, 19) translocation.
Strand-specific (asymmetric) contribution of phosphodiester linkages on RNA polymerase II transcriptional efficiency and fidelity
Liang Xu, Lu Zhang, Jenny Chong, Jun Xu, Xuhui Huang, and Dong Wang
The nonenzymatic RNA polymerization introduces backbone heterogeneity with a mixture of 2′–5′ and 3′–5′ linkages. RNA polymerase II (pol II) is a key modern enzyme responsible for synthesizing 3′–5′–linked RNA with high fidelity. It is unclear how pol II selectively recognizes the 3′–5′ over 2′–5′ linkage. Here, we systematically investigated how phosphodiester linkages of nucleic acids govern pol II transcriptional efficiency and fidelity. We revealed pol II has an asymmetric (strand-specific) recognition of phosphodiester linkage, which may reflect a universal principle of template-dependent genetic information transfer. Our results (pp. E3269–E3276) elucidate essential contributions of the phosphodiester linkage to pol II transcription and provide important understanding on nucleic acid recognition and genetic information transfer during molecular evolution.
Quality control of assembly-defective U1 snRNAs by decapping and 5′-to-3′ exonucleolytic digestion
Siddharth Shukla and Roy Parker
Cellular RNAs undergo assembly with various proteins, which leads to the formation of functional ribonucleoprotein (RNP) complexes. Kinetic defects in the RNP assembly pathway, which affect the rate of RNP formation, can lead to a reduction in the levels of functional RNPs in the cell, and can lead to a disease state, which we classify as an “RNP assembly disease.” One example of this class of diseases is spinal muscular atrophy (SMA), where mutations in the assembly factor survival motor neuron lead to reduced small nuclear (sn)RNA and snRNP levels. Here (pp. E3277–E3286) we describe the decay pathways that regulate snRNA levels and function in the cell, prevention of which could be pertinent as a therapy for SMA.
p53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state
Serif Senturk, Zhan Yao, Matthew Camiolo, Brendon Stiles, Trushar Rathod, Alice M. Walsh, Alice Nemajerova, Matthew J. Lazzara, Nasser K. Altorki, Adrian Krainer, Ute M. Moll, Scott W. Lowe, Luca Cartegni, and Raffaella Sordella
p53 is one of the most intensively studied tumor-suppressor genes. We identified a naturally occurring p53 isoform, generated by an alternative-splicing event, that, although lacking transcriptional activity and canonical tumor suppressor functions, is able to reprogram cells toward the acquisition of metastatic features via a cyclophilin D interaction in the mitochondria matrix (pp. E3287–E3296). Interestingly, this isoform is expressed on tissue injury and in tumors characterized by increased metastatic spread. In some of these tumors, p53-like isoforms are generated by intron 6 mutations. This suggests a possible physiological origin of certain p53 mutations and indicates that mutations resulting in the generation of truncated p53Ψ-like proteins do more than create a 53-null state.
Origin of myofibroblasts in the fibrotic liver in mice
Keiko Iwaisako, Chunyan Jiang, Mingjun Zhang, Min Cong, Thomas Joseph Moore-Morris, Tae Jun Park, Xiao Liu, Jun Xu, Ping Wang, Yong-Han Paik, Fanli Meng, Masataka Asagiri, Lynne A. Murray, Alan F. Hofmann, Takashi Iida, Christopher K. Glass, David A. Brenner, and Tatiana Kisseleva
Liver resident activated hepatic stellate cells (aHSCs), and activated portal fibroblasts (aPFs) are the major source of the fibrous scar in the liver. aPFs have been implicated in liver fibrosis caused by cholestatic liver injury, whereas fibrosis in hepatotoxic liver injury is attributed to aHSCs. However, the contribution of aPFs to cholestatic fibrosis is not well characterized because of difficulties in cell purification and the lack of identified aPF-specific markers. We have developed a novel flow cytometry-based method of aPFs purification from the nonparenchymal cell fraction of collagen-α1(I)-GFP mice and have identified potential aPF-specific markers (pp. E3297–E3305). The goal of this study is to determine whether aPFs contribute to cholestatic liver fibrosis and identify the mechanism(s) of their activation.
Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation
Ageliki Tsagaratou, Tarmo Äijö, Chan-Wang J. Lio, Xiaojing Yue, Yun Huang, Steven E. Jacobsen, Harri Lähdesmäki, and Anjana Rao
5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification produced through the enzymatic activity of TET proteins. Here (pp. E3306–E3315) we present the first genome-wide mapping of 5hmC in T cells during sequential steps of lineage commitment in the thymus and the periphery (thymic DP, CD4 SP, and CD8 SP cells; peripheral naive CD8 and CD4 T cells; and in vitro-differentiated Th1 and Th2 cells). We show that 5hmC is enriched at gene bodies and cell type-specific enhancers, that its levels in the gene body correlate strongly with gene expression and histone modifications, and that its levels change dynamically during the course of T-cell development and differentiation. Our analysis will facilitate increased understanding of the role of 5hmC in T-cell development and differentiation.
Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance
Peter S. Choi, Yulin Li, and Dean W. Felsher
The rationale of targeting specific genetic dependencies for the treatment of cancer has been validated by the promising clinical responses obtained with oncogene-targeted therapies. However, in most cases, the development of resistance remains a major obstacle toward achieving long-term or complete disease remission. Here, we identified mutant β-catenin as a common secondary oncogene addiction pathway in MYC-addicted lymphoma. We demonstrate that, although withdrawal or inhibition of either oncogene is sufficient to induce initial tumor regression, only combined inhibition of both oncogene addiction pathways results in sustained tumor regression. Our results (pp. E3316–E3324) suggest clinical outcomes can be dramatically improved through the simultaneous targeted inhibition of multiple oncogenic addiction pathways.
Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression
Maimon E. Hubbi, Daniele M. Gilkes, Hongxia Hu, Kshitiz, Ishrat Ahmed, and Gregg L. Semenza
Hypoxia-inducible factor 1α (HIF-1α) is required for adaptive changes to low oxygen levels, which include a reduced rate of cell division. However, many cell types continue to proliferate under hypoxic conditions. Here (pp. E3325–E3334), we show that cyclin-dependent kinases 1 and 2 physically and functionally interact with HIF-1α, inhibiting and promoting its degradation by lysosomes, respectively. Cancer cells that proliferate under hypoxia failed to do so when treated with lysosome inhibitors. Our studies reveal that HIF-1α levels are coupled to phases of the cell cycle through lysosomal degradation and identify a novel role for the lysosome as a regulator of cell-cycle progression under hypoxic conditions.
Single-molecule FRET reveals a corkscrew RNA structure for the polymerase-bound influenza virus promoter
Alexandra I. Tomescu, Nicole C. Robb, Narin Hengrung, Ervin Fodor, and Achillefs N. Kapanidis
The genome of the influenza virus consists of eight single-stranded segments of RNA with highly conserved 5′ and 3′ termini. These termini associate to form double-stranded structures that act as promoters for viral transcription and replication. Structural information on the polymerase-bound promoter currently does not exist, so to address this we developed a sensitive single-molecule FRET assay that allowed us to measure distances between fluorescent dyes located on the promoter and map its structure. The distances obtained are consistent with the polymerase-bound RNA promoter being in a “corkscrew” conformation, in which the 5′ and 3′ termini form short hairpins. This work (pp. E3335–E3342) has implications for the development of inhibitors that target polymerase–promoter interactions in this important group of pathogens.
Astrocytes contribute to gamma oscillations and recognition memory
Hosuk Sean Lee, Andrea Ghetti, António Pinto-Duarte, Xin Wang, Gustavo Dziewczapolski, Francesco Galimi, Salvador Huitron-Resendiz, Juan C. Piña-Crespo, Amanda J. Roberts, Inder M. Verma, Terrence J. Sejnowski, and Stephen F. Heinemann
Astrocytes are well placed to modulate neural activity. However, the functions typically attributed to astrocytes are associated with a temporal dimension significantly slower than the timescale of synaptic transmission of neurons. Consequently, it has been assumed that astrocytes do not play a major role in modulating fast neural network dynamics known to underlie cognitive behavior. By creating a transgenic mouse in which vesicular release from astrocytes can be reversibly blocked, we found that astrocytes are necessary for novel object recognition behavior and to maintain functional gamma oscillations both in vitro and in awake-behaving animals. Our findings (pp. E3343–E3352) reveal an unexpected role for astrocytes in neural information processing and cognition.
Modeling first impressions from highly variable facial images
Richard J. W. Vernon, Clare A. M. Sutherland, Andrew W. Young, and Tom Hartley
Understanding how first impressions are formed to faces is a topic of major theoretical and practical interest that has been given added importance through the widespread use of images of faces in social media. We create (pp. E3353–E3361) a quantitative model that can predict first impressions of previously unseen ambient images of faces (photographs reflecting the variability encountered in everyday life) from a linear combination of facial attributes, explaining 58% of the variance in raters’ impressions despite the considerable variability of the photographs. Reversing this process, we then demonstrate that face-like images can be generated that yield predictable social trait impressions in naive raters because they capture key aspects of the systematic variation in the relevant physical features of real faces.
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- Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine
- CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB–MYC involvement
- Strand-specific (asymmetric) contribution of phosphodiester linkages on RNA polymerase II transcriptional efficiency and fidelity
- Quality control of assembly-defective U1 snRNAs by decapping and 5′-to-3′ exonucleolytic digestion
- p53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state
- Origin of myofibroblasts in the fibrotic liver in mice
- Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation
- Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance
- Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression
- Single-molecule FRET reveals a corkscrew RNA structure for the polymerase-bound influenza virus promoter
- Astrocytes contribute to gamma oscillations and recognition memory
- Modeling first impressions from highly variable facial images
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