bims-trasri 2025-12-07 papers

bims-trasri

Biomed News

on Translational stress and ribostasis

Issue of 2025–12–07
eight papers selected by
Cedric Chaveroux, CNRS

Functional Characterization of Hsp110 in Drosophila Reveals its Essential and Dosage-Sensitive Role in Nervous System Integrity.
The Role of STING-Mediated Activation of the Integrated Stress Response in Inflammation-Induced Depletion of Ovarian Reserve.
Inhibition of scheggia/SLC25A1 citrate transporter alleviates XPD deficits.
Dual RNA Polymerase I Inhibition with CX-5461 and BMH-21 Synergizes in Breast Cancer by Activating p53-Dependent Stress.
Small RNA, big defence: Early epigenetic responses to genetic invasion.
Longitudinal assessment of DNA repair signature trajectory in prodromal versus established Parkinson's disease.
Systematic analysis of noncanonical ribosomal protein paralogs does not provide evidence for specialized functions in Drosophila.
m6A Immunoprecipitation from Ribosome-Bound mRNA.

bioRxiv. 2025 Nov 19. pii: 2025.11.18.687301. [Epub ahead of print]

Functional Characterization of Hsp110 in Drosophila Reveals its Essential and Dosage-Sensitive Role in Nervous System Integrity.

Beatriz Rios, Shiyu Xu, Stephen M Farmer, Xin Ye, Lili Ye, Kevin A Morano, Sheng A Zhang.

The Hsp70 molecular chaperone system is the front line of defense in maintaining cellular proteostasis. In eukaryotes, ATP/ADP nucleotide exchange in the Hsp70 chaperone cycle is stimulated by Hsp110, a divergent member of the Hsp70 chaperone superfamily and co-chaperone of Hsp70. Hsp110 is also a known modifier of neurodegenerative and other protein misfolding-related disorders. Biochemical aspects of Hsp110 chaperone functions have been characterized in vitro, and pathway interactions have been extensively characterized genetically in yeast model systems; however, a detailed understanding of its physiological roles in metazoans, particularly in the nervous system has not been carried out. Taking advantage of the single Hsp110-encoding gene in the Drosophila genome, we conducted a comprehensive investigation of its expression and function in this animal model. Notably, Drosophila and human Hsp110 share significant similarity in their sequence, structure, and splicing variants. At the protein level, Hsp110 is ubiquitously expressed, with both cytosolic and nuclear distribution in a tissue-dependent manner. Functionally, while Hsp110 is dispensable for cell proliferation in developing larvae, it is essential for long-term cell survival and normal development of the nervous system, including non-autonomous effects on neuronal differentiation and glial cell migration. Furthermore, despite being identified as a potent suppressor of protein aggregation and neurotoxicity in multiple neurodegenerative diseases, higher levels of Hsp110 are detrimental in flies. Overexpression of Hsp40, another key co-chaperone of Hsp70, can mimic this effect. However, simultaneous overexpression of both Hsp40 and Hsp110 does not further exacerbate their detrimental effect. Together, these results demonstrate a critical role of Hsp110 in neuronal development and cell survival, and further suggest that in vivo, the levels and activities of Hsp110 and Hsp40 co-chaperones need to be properly balanced. Furthermore, this work supports the contention that the Hsp70 chaperone network must be considered as a whole when targeted for potential therapeutic purposes to meet the complex pathophysiological demands in multicellular organisms.

DOI: https://doi.org/10.1101/2025.11.18.687301
FASEB J. 2025 Dec 15. 39(23): e71286

The Role of STING-Mediated Activation of the Integrated Stress Response in Inflammation-Induced Depletion of Ovarian Reserve.

Qiumin Wang, You Wu, Xiaotong Dong, Yuxiu Wu, Yu Dai, Yongzhi Cao, Yanbo Du, Hong Lv, Keke Wei, Lianbao Cao, Lei Yan.

Inflammatory responses within the ovarian microenvironment are increasingly recognized as significant disruptors of ovarian function, yet their specific effects on early follicular development, particularly the activation of primordial follicles, remain poorly understood. In this study, we employ a mouse model of transient lipopolysaccharide (LPS)-induced inflammation to mimic the inflammatory conditions associated with chronic pelvic inflammatory disease (PID) and systemic infections. We demonstrate that LPS stimulation triggers the premature activation of primordial follicles, leading to a depletion of the ovarian reserve. This finding underscores the detrimental impact of inflammation on ovarian health. However, we also identify a protective mechanism mediated by the cGAS-STING pathway, a central regulator of innate immunity and cellular stress responses. Activation of the cGAS-STING pathway effectively inhibits LPS-induced primordial follicle activation, thereby preserving ovarian function. Further mechanistic investigations reveal that the Integrated Stress Response (ISR), a downstream effector of STING signaling, plays a critical role in this protective process. The ISR, orchestrated by kinases such as PERK, modulates cellular homeostasis under stress conditions by phosphorylating eukaryotic initiation factor 2α (eIF2α). Our data show that STING activation induces ISR signaling, which in turn suppresses the overactivation of primordial follicles. To explore the therapeutic potential of this pathway, we utilized STING and ISR agonists, which successfully mitigated LPS-induced primordial follicle activation and preserved ovarian reserve in our experimental model. These findings highlight the dual role of inflammation in ovarian biology: while acute inflammatory stimuli can disrupt follicular quiescence, the cGAS-STING-ISR axis serves as a critical regulatory network to counteract these adverse effects. Our study not only elucidates the molecular mechanisms underlying inflammation-induced ovarian dysfunction but also identifies STING and ISR as promising therapeutic targets for preserving ovarian reserve in women exposed to chronic inflammatory conditions. These insights have significant clinical implications, offering potential strategies to protect ovarian function in patients with inflammatory diseases or those undergoing treatments that compromise ovarian health.

DOI: https://doi.org/10.1096/fj.202502370RR
Sci Rep. 2025 Dec 01. 15(1): 42891

Inhibition of scheggia/SLC25A1 citrate transporter alleviates XPD deficits.

Dong-Gyu Cho, Jean Jung, Ji-Hyun Hwang, Kwang-Wook Choi.

  XPD is an evolutionarily conserved protein critical for DNA repair, transcription, cell cycle, and chromosome segregation. XPD mutations result in complex genetic diseases, including xeroderma pigmentosum (XP). XPD is also implicated in protecting cells from oxidative stress but has not been linked to specific metabolic gene functions. Here, we report an intriguing genetic interaction between Drosophila Xpd and the scheggia (sea) gene encoding the mitochondrial citrate transporter. We show that the reduced eye size by Xpd RNAi in Drosophila is partially restored by the knockdown of sea. sea RNAi suppresses ectopic cell death and DNA damages resulting from Xpd knockdown. To test whether this negative relationship between Xpd and sea can be recapitulated in human cells, we examined the effects of CTPI-2, an inhibitor of the human citrate transporter SLC25A1, on the survival of XPD mutant cells (HD2) carrying the R683W point mutation (XPDR683W). CTPI-2 reduced the survival of UV-irradiated HeLa cells used as control. In contrast, the same level of CTPI-2 increased the viability of HD2 mutant cells exposed to a wide range of UV doses. In response to UV irradiation, HD2 cells are defective in unscheduled DNA synthesis (UDS). CTPI-2 increased the UDS response in HD2 cells. These data indicate that UV-induced DNA damage and lethality of human XPD mutant cells can be suppressed by inhibiting SLC25A1 by CTPI-2, consistent with the genetic interaction between Xpd and sea in Drosophila. This work suggests that XPD is antagonistically related to SLC25A1, and the citrate transporter may be a therapeutic target for alleviating XP syndrome.

Keywords:  Cell survival; Citrate transporter; DNA repair; Drosophila; Growth; SLC25A1; Scheggia gene; UV damage; XPD

DOI:  https://doi.org/10.1038/s41598-025-26976-0
bioRxiv. 2025 Nov 20. pii: 2025.11.19.689351. [Epub ahead of print]

Dual RNA Polymerase I Inhibition with CX-5461 and BMH-21 Synergizes in Breast Cancer by Activating p53-Dependent Stress.

Jonathan Y Chung, Kristen N Nguyen, Bruce A Knutson.

1Hyperactivated ribosomal RNA (rRNA) transcription by RNA polymerase I (Pol I) is a hallmark of cancer and drives elevated ribosome biogenesis required for rapid tumor growth. Several Pol I inhibitors have been identified that induce potent anti-cancer effects. However, clinical application of the first-in-class Pol I inhibitor, CX-5461, has been limited by patient toxicity, which is comparable to other chemotherapies. Identifying synergistic drug combinations offers a promising strategy to maintain on-target anti-cancer effects while minimizing adverse reactions. Synergistic drug combinations involve drugs that enhance each other's effect, enabling dose reduction while preserving efficacy. Synergistic drug combinations of Pol I inhibitors and other anti-cancer agents have been reported; however, it remains unclear whether Pol I inhibitors can synergize with each other. We therefore explored whether two Pol I inhibitors synergize in cancer treatment. We found that CX-5461 and BMH-21 significantly reduced MCF-7 breast cancer cell viability at clinically relevant doses. Combined treatment with these inhibitors led to profound viability defects at sub-micromolar concentrations. Our biochemical analysis showed that CX-5461 and BMH-21 combination therapy enhanced Pol I inhibition and p53 activation compared to monotherapy, promoting growth arrest and apoptosis. Collectively, our findings demonstrate that CX-5461 and BMH-21 are complementary in inhibiting Pol I, activating p53, and suppressing cancer cell growth. Based on these pre-clinical findings, dual Pol I inhibition with CX-5461 and BMH-21 represents a promising therapeutic strategy for treating cancer that is potentially both broadly applicable and tolerable.

DOI: https://doi.org/10.1101/2025.11.19.689351
Quant Plant Biol. 2025 ;6 e34

Small RNA, big defence: Early epigenetic responses to genetic invasion.

Seunghui Mun, Yang Jae Kang, Jungnam Cho.

  Plants are under constant genetic siege. From viruses and bacteria to transposable elements within their genomes, cells must contend with foreign genetic material. Besides these natural threats, modern biotechnology adds complexity by introducing transgenes to plants. While the integration of such DNA can enhance genetic diversity and confer desirable traits, its foreign origin is typically recognised by the plant cell as a signal of invasion and therefore targeted by the repressive mechanisms. Epigenetic silencing is a central strategy and involves the methylation of DNA and histones. A critical trigger of this silencing is the generation of small interfering RNAs (siRNAs). Although the role of siRNAs in maintaining epigenetic silencing is well established, the initial steps that lead to their production remain incompletely understood. This review discusses the key discoveries on how plant cells recognise foreign nucleic acids and initiate epigenetic silencing, contributing to our broader understanding of genome integrity and defence.

Keywords:  No-go RNA decay; RNA quality control; RNA-directed DNA methylation; epigenetic silencing; small RNA

DOI:  https://doi.org/10.1017/qpb.2025.10029
NPJ Parkinsons Dis. 2025 Dec 05. 11(1): 349

Longitudinal assessment of DNA repair signature trajectory in prodromal versus established Parkinson's disease.

Danish Anwer, Nicola Pietro Montaldo, Elva Maria Novoa-Del-Toro, Diana Domanska, Hilde Loge Nilsen, Annikka Polster.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. DNA repair dysfunction and integrated stress response (ISR) dysregulation have been implicated in PD pathophysiology, however, their role during the prodromal phase remains unclear. We analyzed longitudinal blood transcriptomic data from the Parkinson's Progression Markers Initiative to assess DNA repair and ISR genes in healthy individuals, prodromal PD, and those with established PD. Logistic regression classifiers showed that DNA repair and ISR expression distinguished prodromal PD from healthy individuals, with accuracy peaking in later prodromal stages. In contrast, these pathways did not separate established PD from controls, suggesting a more prominent role early in progression. Gene expression variability in prodromal PD was high at baseline but decreased over time, indicating convergence as disease advances. Notably, 50% of DNA repair genes and 74% of ISR genes showed non-linear patterns, suggesting a transient adaptive response fading with progression. Feature importance analysis highlighted several predictors of prodromal PD, including ERCC6, PRIMPOL, NEIL2, and NTHL1. These findings indicate that DNA repair and ISR dysregulation are relevant in prodromal PD and may be biomarkers for early detection and intervention. Future research should validate these results in larger cohorts and evaluate diagnostic and therapeutic potential.

DOI: https://doi.org/10.1038/s41531-025-01194-7
Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2506642122

Systematic analysis of noncanonical ribosomal protein paralogs does not provide evidence for specialized functions in Drosophila.

Katarina Z A Grobicki, Daniel Gebert, Carol Sun, Felipe Karam Teixeira.

  Ribosomes catalyze all protein synthesis, and mutations altering their levels and function underlie many developmental diseases and cancer. Historically considered to be invariant machines, ribosomes differ in composition between tissues and developmental stages, incorporating a diversity of ribosomal proteins (RPs) encoded by duplicated paralogous genes. Here, we use Drosophila to systematically investigate the origins and functions of noncanonical RP paralogs. We show that new paralogs mainly originated through retroposition and that only a few new copies retain coding capacity over time. Although transcriptionally active noncanonical RP paralogs often present tissue-specific expression, we show that the majority of those are not required for either viability or fertility in Drosophila melanogaster. The only exception, RpS5b, which is required for oogenesis, is functionally interchangeable with its canonical paralog, indicating that the RpS5b-/- phenotype results from insufficient ribosomes rather than the absence of an RpS5b-specific, functionally specialized ribosome. Altogether, our results provide evidence that instead of new functions, RP gene duplications provide a means to regulate ribosome levels during development.

Keywords:  germline; ribosome heterogeneity; translational control

DOI:  https://doi.org/10.1073/pnas.2506642122
Methods Enzymol. 2025 ;pii: S0076-6879(25)00401-X. [Epub ahead of print]725 225-253

m6A Immunoprecipitation from Ribosome-Bound mRNA.

Nora T Kiledjian, Morgan J McGrath, Crystal S Conn.

  Here we describe a protocol for correlating a transcript's translational state to its N6-methyladenosine (m6A) status using polysome profiling and m6A immunoprecipitation (IP). Polysome profiling is a technique used to separate out cellular components by density, allowing the visualization of transcripts based on the number of ribosomes bound. The technique uses high ribosome occupancy as a proxy for high translational activity. Transcripts bound by many ribosomes can be isolated from lowly translated transcripts and from those unbound by translational machinery. It has been demonstrated that the RNA modification m6A can alter the stability, localization, and splicing of a transcript. The role that m6A plays in translational selectivity is an established, but still highly debated area in the field. m6A IP is a technique developed to isolate m6A-containing RNA by using an antibody against the m6A modification itself. We have developed this protocol, which pairs polysome profiling with m6A IP in order to broadly characterize the relationship between the presence of m6A modifications and the extent of a transcript's translation.

Keywords:  Epitranscriptomics; N6-Methyladenosine; Polysome profiling; Protein synthesis; RNA modification; m(6)A immunoprecipitation; mRNA translation

DOI:  https://doi.org/10.1016/bs.mie.2025.10.009