EMBO Reports

Tavernarakis, Nektarios

doi: 10.1038/s44319-025-00587-2pmid: 41023442

The current Zeitgeist favouring utilitarian research risks undermining basic research—the very foundation on which innovative technological advances depend.[graphic not available: see fulltext]

Smith, David R

doi: 10.1038/s44319-025-00586-3pmid: 41006899

Like this author, many scientists obsess about their CVs, constantly upgrading and improving them. But at the end of the day, it is just one element of a convincing application.[graphic not available: see fulltext]

Wolinsky, Howard; Breithaupt, Holger; Moran, Yehu

doi: 10.1038/s44319-025-00579-2pmid: 41023440

Several articles questioning the expertise, intentions and professional integrity of several researchers along with weaponized copyright infringement claims is the latest example of how scientists can become targets of so-called dark PR tactics.[graphic not available: see fulltext]

D’Amico, Stephen; Kirillov, Varvara; Liu, Jingxuan; Qiu, Zhijuan; Lei, Xinyuan; Qin, Hong; Sheridan, Brian S; Reich, Nancy C

doi: 10.1038/s44319-025-00563-wpmid: 40859018

Oncogenic KRAS mutations underlie some of the deadliest human cancers. Genetic or pharmacological KRAS inactivation produces mixed outcomes and frequent relapse. Mechanisms of tumor resistance to KRAS inhibition remain poorly understood. We present evidence that STAT3 supports tumor growth following KRAS depletion. Using a conceptual framework of pancreatic ductal adenocarcinoma, we show that cancer cells that survive CRISPR-mediated ablation of mutant KRAS are dependent on STAT3 function to maintain tumorigenicity. Mechanistically, the combined loss of mutant KRAS and STAT3 disrupts a core transcriptional program of cancer cells critical to oncogenic competence. This in turn impairs tumor growth in mice and enhances immune rejection, leading to tumor clearance. We propose that the STAT3 transcriptional program operating in cancer cells enforces their malignant identity, rather than providing classical features of transformation, and shapes cancer persistence following KRAS inactivation. Our findings establish STAT3 as a critical enforcer of oncogenic identity in KRAS-ablated tumors, revealing a key vulnerability.

Liu, Mengting; Cheng, Aoxing; You, Weiyi; Wu, Jiaxin; Dai, Chenxu; Wang, Ting; Wu, Ying; Zhong, Fumei; Shi, Jue; Du, Yingying; Hou, Zhonghuai; Gao, Ping; Ruan, Ke; Yang, Yi; Zhao, Yuzheng; Zhang, Kaiguang; Yang, Zhenye; Guo, Jing

doi: 10.1038/s44319-025-00573-8

Pradhan, Sunil Kumar; Zhang, Hui; Kolobynina, Ksenia G; Rapp, Alexander; Arroyo, Maria; Cardoso, M Cristina

doi: 10.1038/s44319-025-00575-6pmid: 40925959

The flexibility of the spatio-temporal genome replication program during development and disease highlights the regulatory role of plastic epigenetic mechanisms over genetic determinants. Histone post-translational modifications are broadly implicated in replication timing control, yet the specific mechanisms through which individual histone marks influence replication dynamics, particularly in heterochromatin, remain unclear. Here, we demonstrate that H3K36me3 dynamically enriches at pericentromeric heterochromatin, composed of major satellite DNA repeats, prior to replication during mid S phase in mouse embryonic stem cells. By knocking down lysine 36-specific methyltransferases or by targeting the H3K36M oncohistone to pericentromeric heterochromatin, we reduce global or local H3K36me3 levels, respectively, revealing its essential role in preserving the replication timing of constitutive heterochromatin. Loss of H3K36me3 accompanies increased RNA polymerase II serine-5 phosphorylation and lowered major satellite RNA levels, indicating transcriptional dysregulation. Notably, we identify a strand-specific contribution of major satellite forward transcripts in regulating the replication timing of constitutive heterochromatin and maintaining chromatin stability, highlighting the importance of non-coding RNAs as critical regulators of replication timing.

Fung, Tak Shun; Ghosh, Amrapali; Zavala, Maite R; Nichtova, Zuzana; Shukal, Dhavalkumar; Tigano, Marco; Csordas, Gyorgy; Higgs, Henry N; Chakrabarti, Rajarshi

doi: 10.1038/s44319-025-00561-ypmid: 40883511

Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER–mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER–mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.

Kegawa, Yuto; Male, Frances; Jiménez-Munguía, Irene; Blank, Paul S; Mekhedov, Elena; Ward, Gary E; Zimmerberg, Joshua

doi: 10.1038/s44319-025-00565-8pmid: 40973829

The parasite Toxoplasma gondii invades its host cell only after secreting proteins such as invasion-requisite RON2 that inserts into the host cell membrane to establish the moving junction. Electrophysiological recordings at sub-200 µs resolution show a transient increase in host cell membrane conductance following parasite exposure. Transients always precede invasion, but parasites depleted of RON2 generate transients without invading. Thus RON2 is not essential for transient generation. Time-series analysis developed here and applied to the 910,000 data point transient dataset reveal multiple quantal conductance changes in the parasite-induced transient, consistent with rapid insertion, then slower removal, blocking, or inactivation of potential pore components. Quantal steps for wild-type RH strain parasites have a principal mode with Gaussian mean of 0.26 nS, similar in step size to the pore forming protein EXP2, part of the PTEX translocon of malaria parasites. Without RON2 the quantal mean (0.19 nS) is significantly different. Because we observe no parasite invasion without poration, the term “invasion pore” is proposed to describe this transient breach in host cell membrane barrier integrity during invasion.

Male, Frances; Kegawa, Yuto; Blank, Paul S; Jiménez-Munguía, Irene; Sidik, Saima M; Valleau, Dylan; Lourido, Sebastian; Lebrun, Maryse; Zimmerberg, Joshua; Ward, Gary E

doi: 10.1038/s44319-025-00564-9pmid: 40973827

Toxoplasma gondii is an obligate intracellular parasite. Proteins released during host cell invasion from apical secretory organelles known as rhoptries are delivered into the host cell cytosol to perform functions critical for parasite survival and virulence. How these effector proteins move across the host cell plasma membrane is unknown but may involve a previously noted temporary loss of host cell plasma membrane barrier integrity. Here, we use high-speed, multi-wavelength fluorescence imaging to spatially monitor the barrier integrity of the host cell plasma membrane, in real time, during invasion. The data reveal that early in invasion the parasite creates a transient perforation in the host cell membrane. The perforation occurs at the point on the host membrane in contact with the parasite’s apical end. Parasites depleted of any of five proteins known to be required for rhoptry exocytosis are unable to perforate the host cell membrane. These data suggest a model in which perforating agents stored within rhoptries are released onto the host cell at the initiation of invasion to create a conduit for the delivery of rhoptry effector proteins.

Murciano-Julià, Guillem; Vega, Montserrat; Pazo, Esther; Pascual-Serra, Àlex; Alves-Rodrigues, Isabel; Bagudanch, Oriol; Anglada, Roger; Bonet, Núria; Aligué, Rosa; Moreno, Sergio; Oliva, Baldo; Hidalgo, Elena; Ayté, José

doi: 10.1038/s44319-025-00566-7pmid: 40883509

Entry into the cell cycle requires activation of G1 cyclin-dependent kinases (CDKs) and the G1/S transcriptional program. In fission yeast, the MBF complex is the main transcription factor driving early cell-cycle gene expression. MBF-dependent transcription is activated in metaphase and repressed at the end of S phase by a feedback loop involving the cyclin Cig2 and co-repressors Nrm1 and Yox1. While replicative stress inactivates Yox1 via phosphorylation, the mechanism that activates MBF during an unperturbed cell cycle remains unclear. Here, we identify Nrm1 as the key target of cell cycle regulation in a two-step control mechanism. First, CDK1 phosphorylates Nrm1 in metaphase, leading to its release—along with Yox1—from chromatin. Second, unphosphorylated Nrm1, generated either by dephosphorylation or de novo synthesis, is degraded during anaphase, preventing its re-association with MBF until the end of the next S phase. Together, these parallel pathways create a precisely timed window of MBF activation, ensuring proper cell cycle progression and preserving genomic stability.