Molecular Biology

Systematic yeast two-hybrid screening identifies novel functions for SET1C/COMPASS

1. Pierre Luciano
2. Kihyun Park
3. Stéphane Audebert
4. Luc Camoin
5. Carlos A Niño
6. Da Kyeong Park
7. Isabella E Maudlin
8. Marion Dubarry
9. Lara Lee
10. Marlene Oeffinger
11. Jean D Beggs
12. Young Hye Kim
13. Jaehoon Kim
14. Bernhard Dichtl
15. Vincent Géli

• Curated by eLife

  eLife Assessment

  This study uses the yeast two-hybrid assay to identify proteins that may interact with yeast Set1 and other subunits of COMPASS/Set1C, the histone H3K4 methyltransferase, providing also some evidence for Set1 sumoylation and a role of SET1C methylating other factors in vitro. The results are valuable, and they should contribute to understanding the functions of the conserved SET1C complex, as they suggest potential functional connections with RNA biogenesis, chromatin remodeling, and non-histone methylation, whose implications would yet need to be explored. Nevertheless, apart from the fact that only a small subset of the Y2H interactions is further examined, the validating experiments are only partial or inconclusive, the strength of evidence being at this point incomplete.

Reviewed by eLife

Structural basis for the folding of PINK1 by the HSP90–CDC37 chaperone complex

1. Kei Okatsu
2. Hayato Yamamoto
3. Akinori Okamoto
4. Shinya H Goto
5. Yumiko Nishimoto
6. Yukihiko Sugita
7. Takeshi Noda
8. Shuya Fukai

• Curated by eLife

  eLife Assessment

  This study presents a high-quality cryo-EM structure of the human kinase PINK1 in complex with the HSP90-CDC37 chaperone complex, capturing a partially folded intermediate in which the C-lobe and C-terminal extension are structured while the N-lobe remains unfolded and engaged by the HSP90 clamp. The structural data are broadly consistent with a recently published structure of the same complex, providing useful insight into early steps of PINK1 maturation and highlighting residues linked to familial Parkinson's disease. However, the mechanistic conclusions remain incomplete because the manuscript does not experimentally validate key hypotheses raised by the structure, including the functional roles of the C-lobe interface, the HPNI motif, the C-terminal extension, or the proposed competition between HSP90 and TOM20.

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Global molecular landscape of early MASLD progression in human obesity

1. Qing Zhao
2. William De Nardo
3. Ruoyu Wang
4. Yi Zhong
5. Umur Keles
6. Gabriele Sakalauskaite
7. Li Na Zhao
8. Huiyi Tay
9. Sonia Youhanna
10. Mengchao Yan
11. Ye Xie
12. Youngrae Kim
13. Sungdong Lee
14. Rachel Liyu Lim
15. Guoshou Teo
16. Pradeep Narayanaswamy
17. Paul R Burton
18. Volker M Lauschke
19. Hyungwon Choi
20. Matthew J Watt
21. Philipp Kaldis

• Curated by eLife

  eLife Assessment

  The authors provide a useful resource and approach to identify early-stage biomarkers of MASLD progression, notably when no other apparent symptoms have arisen. The strength of evidence to support new MASLD signatures is solid as the work combines metabolomic and transcriptomic measures in blood and liver biopsies.

  [Editors' note: this paper was reviewed by Review Commons.]

Reviewed by eLife, Review Commons

Distinct Mechanisms for Inhibition of SARS-CoV-2 Main Protease: Dimerization Promoted by Peptidomimetic Inhibitors and Disrupted by Ebselen

1. Chengxi Liu
2. Qinyu Jia
3. Chang Zhao
4. Zhong-Ping Yao

• Curated by eLife

  eLife Assessment

  This important study provides a comprehensive comparison of the mechanisms through which different inhibitors affect the SARS-CoV-2 main protease, a pivotal antiviral drug target, and suggests a potentially broad-spectrum strategy to inhibit this critical viral enzyme by disrupting its dimerization states. However, whereas the biophysical analyses of the dimer stability are convincing, evidence supporting this new mode of mechanism to inhibit the main protease is incomplete and would benefit from a correlation of the biophysical observations with functional activity. With the functional validation part strengthened, this work would be of interest to biochemists and virologists working on anti-coronavirus drug discovery.

Reviewed by eLife

Sperm motility in mice with oligo-astheno-teratozoospermia restored by in vivo injection and electroporation of naked mRNA

1. Charline Vilpreux
2. Paul Fourquin
3. Guillaume Martinez
4. Magali Court
5. Florence Appaix
6. Jean Luc Duteyrat
7. Maxime Henry
8. Julien Vollaire
9. Camille Ayad
10. Altan Yavuz
11. Geneviève Chevalier
12. Lisa De Macedo
13. Sofia Andrade Rebelo
14. Edgar Del Llano
15. Célia Tebbakh
16. Zine Eddine Kherraf
17. Emeline Lambert
18. Sekou Ahmed Conté
19. Zeina Wehbe
20. Elsa Giordani
21. Veronique Josserand
22. Jacques Brocard
23. Charles Coutton
24. Bernard Verrier
25. Pierre F Ray
26. Corinne Loeuillet
27. Christophe Arnoult
28. Jessica Escoffier

• Curated by eLife

  eLife Assessment

  This study reports an mRNA-based strategy for restoring sperm motility in a mouse model of monogenic male infertility. The work is technically innovative and potentially valuable, as it demonstrates feasibility of in vivo testicular mRNA delivery without genomic integration of foreign DNA. However, although partial recovery of sperm motility is supported, the evidence for meaningful restoration of fertility remains incomplete, with weak IVF outcomes and difficult-to-interpret ICSI results. In addition, mechanistic questions regarding the persistence of mRNA and the specificity of germ-cell targeting remain insufficiently resolved, limiting the strength of the authors' conclusions.

Reviewed by eLife

EPB41L4A-AS1 long noncoding RNA acts in both cis- and trans-acting transcriptional regulation and controls nucleolar biology

1. Alan Monziani
2. Juan Pablo Unfried
3. Todor Cvetanovic
4. Igor Ulitsky

• Curated by eLife

  eLife Assessment

  This paper provides important findings towards understanding the role of the lncRNA EPB41L4A-AS1 in a human cell line. The data is generally convincing, supported by extensive and clever integrative analysis. The work provides insights into how this lncRNA regulates gene expression via complex mechanisms; however the biological relevance awaits validation in other models.

Reviewed by eLife

FRG1 Regulates Nonsense-Mediated mRNA Decay by Modulating UPF1 Levels

1. Ananya Palo
2. Talina Mohapatra
3. Anamika Singh
4. Shithij Thalakkat
5. Suryasikha Mohanty
6. Rajeeb Kumar Swain
7. Manjusha Dixit

• Curated by eLife

  eLife Assessment

  This useful study by Palo et al proposes that FRG1 functions as a negative regulator of Nonsense-Mediated mRNA decay (NMD) by associating with the exon junction complex (EJC) and destabilizing UPF1 independently of DUX4. The authors present solid evidence to dissect the relationship between FRG1 and DUX4 in NMD. However, the evidence to support the claim that FRG1 is a component of the EJC or the NMD machinery is incomplete.

Reviewed by eLife

Impacts of DNA Methylation on H2A.Z Deposition and Nucleosome Stability

1. Rochelle M Shih
2. Yasuhiro Arimura
3. Hide A Konishi
4. Hironori Funabiki

• Curated by eLife

  eLife Assessment

  This study provides valuable mechanistic insight into the mutually exclusive distributions of the histone variant H2A.Z and DNA methylation by testing two hypotheses: (i) that DNA methylation destabilizes H2A.Z nucleosomes, thereby preventing H2A.Z retention, and (ii) that DNA methylation suppresses H2A.Z deposition by ATP-dependent chromatin remodelling complexes. Through a series of well-designed and carefully executed experiments, findings are presented in support of both hypotheses. However, the evidence in support of either hypothesis is incomplete, so that the proposed mechanisms underlying the enrichment of H2A.Z on unmethylated DNA remain somewhat speculative.

Reviewed by eLife

Specialization of ubiquitin ligases to distinct nucleic acid sensors

1. Ibrahim Syed
2. Sheng Chen
3. David J. Peeler
4. Paul F. McKay
5. Marco A. Briones-Orta
6. Jennifer A. Bohn
7. Robin J. Shattock
8. Daniel Gonçalves-Carneiro

Reviewed by Review Commons

The chromatin remodeller CHD4 regulates transcription factor binding to both prevent activation of silent enhancers and maintain active regulatory elements

1. Andria Koulle
2. Oluwaseun Ogundele
3. Devina Shah
4. India Baker
5. Maya Lopez
6. David Lando
7. Nicola Reynolds
8. Ramy Ragheb
9. Ernest D Laue
10. Brian Hendrich

• Curated by eLife

  eLife Assessment

  This work offers important insights into the protein CHD4's function in chromatin remodeling and gene regulation in embryonic stem cells, supported by extensive biochemical, genomic, and imaging data. The use of an inducible degron system allows precise functional analysis, and the datasets generated represent a key resource for the field. The revised study offers compelling evidence and makes a significant contribution to understanding CHD4's role in epigenetic regulation. This work will be of interest to the epigenetics and stem biology fields.

Reviewed by eLife