Molecular Biology

Cryo-EM structure of the CBC-ALYREF complex

1. Bradley P. Clarke
2. Alexia E. Angelos
3. Menghan Mei
4. Pate S. Hill
5. Yihu Xie
6. Yi Ren

• Curated by eLife

  eLife assessment

  This important study reports the cryo-electron microscopy structure of a multi-protein complex that recognizes the 5'-end cap of mRNAs and plays a critical role in mRNA export. The structural analyses and biochemical assays in this study provide convincing evidence to support the major claims of the authors, although the inclusion of more functional characterizations in cell-based systems would have strengthened the study. This paper would be of interest to structural biologists and RNA biologists working on mRNA metabolism.

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Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation

1. Wayne Mitchell
2. Ludger JE Goeminne
3. Alexander Tyshkovskiy
4. Sirui Zhang
5. Julie Y Chen
6. Joao A Paulo
7. Kerry A Pierce
8. Angelina H Choy
9. Clary B Clish
10. Steven P Gygi
11. Vadim N Gladyshev

• Curated by eLife

  eLife assessment

  This important study reports comprehensive multi-omics data on the changes induced in young and aged male mouse tail fibroblasts after treatment with chemical reprogramming factors. The authors provide solid evidence to support their claim that chemical reprogramming factors induce changes consistent with a reduction of cellular 'biological' age (e.g., correlations with established aging markers in whole tissues).

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A cryo-ET study of ciliary rootlet organization

1. Chris van Hoorn
2. Andrew P. Carter

• Curated by eLife

  eLife assessment

  This fundamental study offers a compelling molecular model for the organization of rootlets, a critical organelle that links cilia to the basal body, ensuring proper anchoring. While previous research has explored rootlet structure and organization, this study delivers an unprecedented level of resolution, important to the centrosome and cilia field. The model proposed by the authors will serve as a reference for future studies.

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Multiple cullin-associated E3 ligases regulate cyclin D1 protein stability

1. Ke Lu
2. Ming Zhang
3. Guizheng Wei
4. Guozhi Xiao
5. Liping Tong
6. Di Chen

• Curated by eLife

  eLife assessment

  This paper is of interest to cell biologists studying the mechanisms of protein posttranslational modifications. The study investigates Cullin-RING ubiquitin E3 ligases (CRLs) that regulate cyclin D1 protein stability in cells by utilizing siRNA screening and ectopic expression approaches. By screening a siRNA library containing different E3 ligases, the authors identified a previously uncharacterized combination of Cullin 1-7 and associated E3 ligases (Keap1-CUL3, DDB2-CUL4A/4B, WSB2-CUL2/5, and RBX1-CUL1-7) that are important for cyclin D1 ubiquitination and proteasome-mediated degradation.

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Protein Kinase Structure and Dynamics: Role of the αC-β4 Loop

1. Jian Wu
2. Nisha A. Jonniya
3. Sophia P. Hirakis
4. Cristina Olivieri
5. Gianluigi Veglia
6. Alexandr P. Kornev
7. Susan S. Taylor

• Curated by eLife

  eLife assessment

  This valuable study draws attention to the importance of a previously overlooked structural motif in kinase regulation. While the data presented are intriguing and mostly solid, further analysis and additional experiments will be needed in the future to support the authors' hypothesis. The work will be of interest to protein biochemists and enzymologists with an interest in kinases and allostery.

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SPAG7 deletion causes intrauterine growth restriction, resulting in adulthood obesity and metabolic dysfunction

1. Stephen E Flaherty
2. Olivier Bezy
3. Brianna LaCarubba Paulhus
4. LouJin Song
5. Mary Piper
6. Jincheng Pang
7. Yoson Park
8. Shoh Asano
9. Yu-Chin Lien
10. John D Griffin
11. Andrew Robertson
12. Alan Opsahl
13. Dinesh Hirenallur-Shanthappa
14. Youngwook Ahn
15. Evanthia Pashos
16. Rebecca A Simmons
17. Morris J Birnbaum
18. Zhidan Wu

• Curated by eLife

  eLife assessment

  This study combines molecular genetics and target validation to discover genes involved in obesity and determine their role. It was unanimously agreed that the work is important in terms of significance as it has conceptual and practical implications beyond metabolism, including embryonic and placental development. The strength of evidence is convincing from the use of their forward genetic screen in mice.

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PI3Kα inhibition blocks osteochondroprogenitor specification and the hyper-inflammatory response to prevent heterotopic ossification

1. José Antonio Valer
2. Alexandre Deber
3. Marius Wits
4. Carolina Pimenta-Lopes
5. Marie-José Goumans
6. José Luis Rosa
7. Gonzalo Sánchez-Duffhues
8. Francesc Ventura

• Curated by eLife

  eLife assessment

  This paper presents valuable insights into the implication of PI3Ka in heterotopic ossification (HO), and illustrates a potential therapeutic efficacy of BYL719 in suppressing HO within a murine model of Fibrodysplasia Ossificans Progressiva. While certain data are novel and compelling, others exhibit redundancies with prior publications and are inadequate in terms of methodology and presentation. Additionally, elucidating the precise molecular mechanisms of BYL719's action is imperative for a comprehensive understanding.

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Scaling of an antibody validation procedure enables quantification of antibody performance in major research applications

1. Riham Ayoubi
2. Joel Ryan
3. Michael S Biddle
4. Walaa Alshafie
5. Maryam Fotouhi
6. Sara Gonzalez Bolivar
7. Vera Ruiz Moleon
8. Peter Eckmann
9. Donovan Worrall
10. Ian McDowell
11. Kathleen Southern
12. Wolfgang Reintsch
13. Thomas M Durcan
14. Claire Brown
15. Anita Bandrowski
16. Harvinder Virk
17. Aled M Edwards
18. Peter McPherson
19. Carl Laflamme

• Curated by eLife

  eLife assessment

  Antibodies are some of the most critical tools in biomedical research. However, their quality and specificity vary significantly. This fundamental study provides guidelines for how the quality of an antibody should be assessed and recorded and provides compelling data on the selected antibodies. This paper will be of interest to researchers working in experimental cell biology.

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An anciently diverged family of RNA binding proteins maintain correct splicing of ultra-long exons through cryptic splice site repression

1. Chileleko Siachisumo
2. Sara Luzzi
3. Saad Aldalaqan
4. Gerald Hysenaj
5. Caroline Dalgliesh
6. Kathleen Cheung
7. Matthew R Gazzara
8. Ivaylo D Yonchev
9. Katherine James
10. Mahsa Kheirollahi Chadegani
11. Ingrid Ehrmann
12. Graham R Smith
13. Simon J Cockell
14. Jennifer Munkley
15. Stuart A Wilson
16. Yoseph Barash
17. David J Elliott

• Curated by eLife

  eLife assessment

  This study combines CLIP, RNA-seq, and splicing assays with manipulation of RBMX and its homologs RBMY and RBMXL2 to show that the RBMX family suppresses the recognition of cryptic splicing within long exons. The study is important in that it puts forward the intriguing claim that the RBMX family is responsible for the cryptic splice site repression in ultra-long exons. The methods, data, and analyses supporting the claims are solid, broadly supporting the claims, with some weaknesses. The generalization of the findings is somewhat overstated but could be strengthened by deeper statistical integration of the RNA-seq and CLIP datasets.

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Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain

1. Gabriella O. Estevam
2. Edmond M. Linossi
3. Christian B. Macdonald
4. Carla A. Espinoza
5. Jennifer M. Michaud
6. Willow Coyote-Maestas
7. Eric A. Collisson
8. Natalia Jura
9. James S. Fraser

• Curated by eLife

  eLife assessment

  This manuscript describes a deep mutational scanning study of the kinase domain of the MET receptor tyrosine kinase. The study yields a valuable catalog of essentially all possible deleterious mutations in this portion of the receptor., with convincing evidence. The manuscript will be of interest to researchers working in the field of receptor tyrosine kinases.

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Identification of a carbohydrate recognition motif of purinergic receptors

1. Lifen Zhao
2. Fangyu Wei
3. Xinheng He
4. Antao Dai
5. Dehua Yang
6. Hualiang Jiang
7. Liuqing Wen
8. Xi Cheng

• Curated by eLife

  eLife assessment

  Purines are native molecules that affect processes in the immune system, among others. The manuscript describes a valuable investigation of the mode of binding of purines, especially their carbohydrate moiety, to human receptors in cell culture and by computer-based modelling. Solid evidence is presented about the way purines interact with and activate two receptors.

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SUMOylation of Bonus, the Drosophila homolog of Transcription Intermediary Factor 1, safeguards germline identity by recruiting repressive chromatin complexes to silence tissue-specific genes

1. Baira Godneeva
2. Maria Ninova
3. Katalin Fejes-Toth
4. Alexei Aravin

• Curated by eLife

  eLife assessment

  This important study advances our knowledge of Drosophila Bonus, the sole ortholog of the mammalian transcriptional regulator Tif1. Solid evidence, both in vivo and in vitro, shows how SUMOylation controls the function of the Bonus protein and what the impact of SUMOylation on the function of Bonus protein in the ovary is.

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Systematic Analysis of Network-driven Adaptive Resistance to CDK4/6 and Estrogen Receptor Inhibition using Meta-Dynamic Network Modelling

1. Anthony Hart
2. Sung-Young Shin
3. Lan K. Nguyen

• Curated by eLife

  eLife assessment

  This manuscript presents a useful method for a comprehensive numerical simulation to systematically characterise the effect of heterogeneity in either the initial conditions or the biophysical parameters on the dynamic behaviour of protein signalling networks. Nevertheless, the presentation and detail of their model appear incomplete to fully support the main claims of the manuscript.

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Mitochondrial genomes of Pleistocene megafauna retrieved from recent sediment layers of two Siberian lakes

1. Peter Andreas Seeber
2. Laura Batke
3. Yury Dvornikov
4. Alexandra Schmidt
5. Yi Wang
6. Kathleen Stoof-Leichsenring
7. Katie Moon
8. Samuel H Vohr
9. Beth Shapiro
10. Laura S Epp

• Curated by eLife

  eLife assessment

  This work presents convincing evidence for the presence of wooly mammoth/rhinoceros ancient environmental DNA (aeDNA) far from the time likely to host living individuals: what is effectively a genetic version of a geological inclusion. These are important findings that will have ramifications for the interpretation and conclusions extracted from aeDNA more generally.

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Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis

1. Kyounghee Min
2. Batuhan Yenilmez
3. Mark Kelly
4. Dimas Echeverria
5. Michael Elleby
6. Lawrence M Lifshitz
7. Naideline Raymond
8. Emmanouela Tsagkaraki
9. Shauna M Harney
10. Chloe DiMarzio
11. Hui Wang
12. Nicholas McHugh
13. Brianna Bramato
14. Brett Morrison
15. Jeffery D Rothstein
16. Anastasia Khvorova
17. Michael P Czech

• Curated by eLife

  eLife assessment

  This convincing manuscript represents a valuable advance in understanding the role of MCT1 – a transporter for lactate and other organic anions – in hepatocytes and hepatic stellate cells in the liver. The authors also generate exciting new tools to investigate hepatic stellate cell biology, and these may have much broader applications, but future studies are required to validate these new tools.

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SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury

1. Xiaoyan Yang
2. Hsiang-Chun Chang
3. Yuki Tatekoshi
4. Amir Mahmoodzadeh
5. Maryam Balibegloo
6. Zeinab Najafi
7. Rongxue Wu
8. Chunlei Chen
9. Tatsuya Sato
10. Jason Shapiro
11. Hossein Ardehali

• Curated by eLife

  eLife assessment

  In this study, Yang et al. have shown that SIRT2 has adverse effects on the heart in response to injury. Further, they demonstrate that deletion of Sirt2 is protective through stabilization and increased nuclear translocation of NRF2, which leads to increased expression of antioxidant genes. They also show that pharmacological inhibition of SIRT2 protects the heart against the development of cardiac hypertrophy.

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Gle1 is required for tRNA to stimulate Dbp5 ATPase activity in vitro and promote Dbp5-mediated tRNA export in vivo in Saccharomyces cerevisiae

1. Arvind Arul Nambi Rajan
2. Ryuta Asada
3. Ben Montpetit

• Curated by eLife

  eLife assessment

  The work is a valuable contribution to understanding the mechanism of nuclear export of tRNA in budding yeast. The authors present solid evidence that Dbp5 functions in parallel with Los1 and Msn5 in tRNA export, in a manner dependent on Gle1 for activation of its ATPase activity but independently of Mex67, Dbp5's partner in mRNA export. It further presents biochemical evidence that Dbp5 can bind tRNA but that Gle1 and InsP6 are required for activating ATP hydrolysis by the Dbp5-tRNA complex, suggesting a possible mechanism for tRNA export by Dbp5.

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Gle1 is required for tRNA to stimulate Dbp5 ATPase activity in vitro and promote Dbp5-mediated tRNA export in vivo in Saccharomyces cerevisiae

1. Arvind Arul Nambi Rajan
2. Ryuta Asada
3. Ben Montpetit

• Curated by eLife

  eLife assessment

  The work is a valuable contribution to understanding the mechanism of nuclear export of tRNA in budding yeast. The authors present solid evidence that Dbp5 functions in parallel with Los1 and Msn5 in tRNA export, in a manner dependent on Gle1 for activation of its ATPase activity but independently of Mex67, Dbp5's partner in mRNA export. It further presents biochemical evidence that Dbp5 can bind tRNA but that Gle1 and InsP6 are required for activating ATP hydrolysis by the Dbp5-tRNA complex, suggesting a possible mechanism for tRNA export by Dbp5.

Reviewed by eLife

Rapid cloning-free mutagenesis of new SARS-CoV-2 variants using a novel reverse genetics platform

1. Enja Tatjana Kipfer
2. David Hauser
3. Martin J Lett
4. Fabian Otte
5. Lorena Urda
6. Yuepeng Zhang
7. Christopher MR Lang
8. Mohamed Chami
9. Christian Mittelholzer
10. Thomas Klimkait

• Curated by eLife

  eLife assessment

  This study describes CLEVER, an improved method for fast and efficient rescue and mutagenesis of SARS-CoV2. While the principle of this method is not new, this work significantly improves upon existing protocols, providing an important advancement in the field of viral infectious clones. Convincing proof-of-concept experiments were performed that demonstrate the utility and efficiency of the method.

Reviewed by eLife

No Ramp Needed: Spandrels, Statistics, and a Slippery Slope

• Curated by eLife

  eLife assessment

  This is an important contribution to the origins and translational consequences of the relatively low rate of translation elongation in the first ∼30-50 codons of genes in most organisms. The authors provide convincing evidence that the prevalence of rare codons in the first ~40 codons in yeast is due to the relatively recent evolution of these coding sequences, or of lower purifying selection operating on them, and that a preponderance of codons encoded by rare tRNAs near the N-terminus is not associated with higher translational efficiency in the manner proposed by the "translational ramp" hypothesis. The work is incomplete in that the results of reporter assays may have been confounded by alterations of mRNA sequence or structure that could have influenced their translation or mRNA stability; that the work cannot fully account for a greater enrichment of slowly translated codons in N-terminal vs. C-terminal regions; and that the work does not resolve whether translation elongation through N-terminal coding is truly slow.

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