Molecular Biology

PDGFRα signaling regulates Srsf3 transcript binding to affect PI3K signaling and endosomal trafficking

1. Thomas E Forman
2. Marcin P Sajek
3. Eric D Larson
4. Neelanjan Mukherjee
5. Katherine A Fantauzzo

• Curated by eLife

  eLife Assessment

  This fundamental work provides new mechanistic insight in regulation of PDGF signaling through splicing controls. The evidence is compelling to demonstrate functional involvement of Srsf3, an RNA binding protein to this new and interesting mechanism. The work will be of broad interest to developmental biologists in general and molecular biologists/biochemists in the field of growth factor signaling and RNA processing.

Reviewed by eLife

An ancient competition for the conserved branchpoint sequence influences physiological and evolutionary outcomes in splicing

1. Karen Larissa Pereira de Castro
2. Jose M Abril
3. Kuo-Chieh Liao
4. Haiping Hao
5. John Paul Donohue
6. William K Russell
7. W Samuel Fagg

• Curated by eLife

  eLife Assessment

  This important manuscript provides insights into the competition between Splicing Factor 1 (SF1) and Quaking (QKI) for binding at the ACUAA branch point sequence in a model intron, regulating exon inclusion. The study employs rigorous transcriptomic, proteomic, and reporter assays, with both mammalian cell culture and yeast models. Nevertheless, while the data are convincing, broadening the analysis to additional exons and narrowing the manuscript's title to better align with the experimental scope would strengthen the work.

Reviewed by eLife

eIF3 engages with 3’-UTR termini of highly translated mRNAs

1. Santi Mestre-Fos
2. Lucas Ferguson
3. Marena Trinidad
4. Nicholas T. Ingolia
5. Jamie H. D. Cate

• Curated by eLife

  eLife Assessment

  This valuable study reveals extensive binding of eukaryotic translation initiation factor 3 (eIF3) to the 3' untranslated regions (UTRs) of efficiently translated mRNAs in human pluripotent stem cell-derived neuronal progenitor cells. The authors provide solid evidence to support their conclusions, although this study may be enhanced by addressing potential biases of techniques employed to study eIF3:mRNA binding and providing additional mechanistic detail. This work will be of significant interest to researchers exploring post-transcriptional regulation of gene expression, including cellular, molecular, and developmental biologists, as well as biochemists.

Reviewed by eLife

Acute Activation of Genes Through Transcriptional Condensates Impact Non-target Genes in a Chromatin Domain

1. Darshika Bohra
2. Zubairul Islam
3. Sundarraj Nidharshan
4. Aprotim Mazumder
5. Dimple Notani

• Curated by eLife

  eLife Assessment

  The authors use single molecule imaging and in vivo loop-capture genomic approaches to investigate estrogen mediated enhancer-target gene activation in human cancer cells. These potentially important results suggest that ER-alpha can, in a temporal delay, activate a non-target gene TFF3, which is in proximity to the main target gene TFF1, even though the estrogen responsive enhancer does not loop with the TFF3 promoter. To explain these results, the authors invoke a transcriptional condensate model. The reviewers were split on the strength and interpretation of the evidence presented, which is considered incomplete at this stage. We encourage a revision which buttresses the findings with additional control experiments and careful consideration of alternative explanations and mathematical models. Further, the depth of the discussion on existing literature could be improved. This work will be of interest to those studying transcriptional gene regulation and hormone-aggravated cancers.

Reviewed by eLife

N6-methyladenosine in DNA promotes genome stability

1. Brooke A Conti
2. Leo Novikov
3. Deyan Tong
4. Qing Xiang
5. Savon Vigil
6. Thomas J McLellan
7. Chuong Nguyen
8. Nancy De La Cruz
9. Reshma T Veettil
10. Prashant Pradhan
11. Parag Sahasrabudhe
12. Jason D Arroyo
13. Lei Shang
14. Benjamin R Sabari
15. David J Shields
16. Mariano Oppikofer

• Curated by eLife

  eLife Assessment

  This manuscript reports important findings that the methyltransferase METTL3 is involved in the repair of abasic sites and uracil in DNA, mediating resistance to floxuridine-driven cytotoxicity. Convincing evidence shows the involvement of m6A in DNA based on single cell imaging and mass spec data. The authors present evidence that the m6A signal does not result from bacterial contamination or RNA, but the text does not make this overly clear.

Reviewed by eLife

Saccharomyces cerevisiae Rev7 promotes non-homologous end-joining by blocking Mre11 nuclease and Rad50’s ATPase activities and homologous recombination

1. Sugith Badugu
2. Kshitiza M Dhyani
3. Manoj Thakur
4. Kalappa Muniyappa

• Curated by eLife

  eLife Assessment

  This manuscript reports important data providing evidence that a 42 amino acid region of Rev7 is necessary and sufficient for interaction with the Rad50-Mre11-Xrs2 complex in budding yeast. The authors conclude that Rev7 inhibits the Rad50 ATPase and the Mre11 nuclease with the exception of ssDNA exonuclease activity. The convincing data largely support the conclusions, although the effect of Rev7 on homologous recombination is less well documented and the observed effect on resection is moderate. Specifically, the result that the Rev7 C-terminal truncation lacking the 42 amino acid region still suppresses homologous recombination is unexpected and unexplained.

Reviewed by eLife

Human immunodeficiency virus-1 induces host genomic R-loop and preferentially integrates its genome near the R-loop regions

1. Kiwon Park
2. Dohoon Lee
3. Jiseok Jeong
4. Sungwon Lee
5. Sun Kim
6. Kwangseog Ahn

• Curated by eLife

  eLife Assessment

  This study presents two main findings regarding HIV-1 genomic integration. The first, based on convincing evidence in primary cell models, is that HIV-1 induces R loop formation, though the viral driver of this process remains undefined. The second, based on model cell systems with limited physiological relevance to HIV-1, is that a portion of HIV-1 genomes integrates in the vicinity of where R loops form. This finding has the potential to offer fundamental insight into HIV-1 integration, but the strength of the presented evidence was viewed as incomplete and needing additional validation by more direct experimental methods in order to understand what the mechanistic relationship between the formation of R loops and HIV-1 integration is.

Reviewed by eLife

Ensemble Refinement of mismodeled cryo-EM RNA Structures Using All-Atom Simulations

1. Elisa Posani
2. Pavel Janos
3. Daniel Haack
4. Navtej Toor
5. Massimiliano Bonomi
6. Alessandra Magistrato
7. Giovanni Bussi

Reviewed by PREreview

Structural and functional insights into Cdc45 recruitment by Sld7– Sld3 for CMG complex formation

1. Hao Li
2. Izumi Ishizaki
3. Koji Kato
4. XiaoMei Sun
5. Sachiko Muramatsu
6. Hiroshi Itou
7. Toyoyuki Ose
8. Hiroyuki Araki
9. Min Yao

• Curated by eLife

  eLife Assessment

  This valuable paper describes the crystal structure of a complex of Sld3-Cdc45-binding domain (CBD) with Cdc45, which is essential for the assembly of an active Cdc45- MCM-GINS (CMG) double hexamers at the replication origin. Although the results shown in the paper are of interest to researchers in DNA replication and genome stability, the biochemical analysis of protein-protein interaction and DNA binding is incomplete, and the paper needs additional data and revised discussion.

Reviewed by eLife

Genetic stability of Mycobacterium smegmatis under the stress of first-line antitubercular agents

1. Dániel Molnár
2. Éva Viola Surányi
3. Tamás Trombitás
4. Dóra Füzesi
5. Rita Hirmondó
6. Judit Toth

• Curated by eLife

  eLife Assessment

  This useful study reports on the impact of antibiotic pressure on the genomic stability of the mc2155 strain of Mycobacterium smegmatis, a model for Mycobacterium tuberculosis. The findings of the study indicate that exposure to antibiotics did not lead to the development of new adaptive mutations in controlled laboratory environments, challenging the notion that antibiotic resistance arises from drug-induced microevolution. The genomic analysis provides detailed insights into the stability of M. smegmatis following exposure to standard TB treatment antibiotics, and the evidence suggesting that antibiotic pressure does not contribute to the emergence of new adaptive mutations is solid.

Reviewed by eLife