Chronic replication stress-mediated genomic instability disrupts placenta development in mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Abstract Abnormal placentation drives many pregnancy-related pathologies and poor fetal outcomes, but the underlying molecular causes are understudied. Here, we show that persistent replication stress due to mutations in MCM2-7 replicative helicase disrupts reduces embryo viability mice. MCM-deficient embryos exhibited normal morphology their placentae had a drastically diminished junctional zone (JZ). Whereas cell proliferation labyrinth (LZ) remained unaffected, JZ was reduced, independent of death during early development. Mouse trophoblast stem cells (TSCs) with high genomic instability failed maintain stemness, suggesting affects initial progenitor pool manner preferentially impacts developing JZ. Genetically increasing chromatin-bound MCM levels mutants rescued placental defects viability. Developing female mice deficient for FANCM, protein involved replication-associated DNA repair, also These findings indicate stress-induced compromises outcomes by impairing placentation.

Language: Английский

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Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 19, 2025

Abstract Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such acute respiratory distress syndrome, sepsis, trauma ischemia lead to the aberrant cytosolic accumulation massive release of nucleic are detected by antiviral innate receptors in endosome or cytosol. Activation for deoxyribonucleic ribonucleic triggers inflammation, a major contributor morbidity mortality critically ill patients. In past decade, there has been growing recognition therapeutic potential targeting acid sensing critical care. This review summarizes current knowledge ischemia. Given extensive research on common pathological conditions like cancer, autoimmune disorders, metabolic disorders aging, we provide comprehensive summary beyond illness offer insights may inform its role conditions. Additionally, discuss strategies specifically target sensing. By examining sources, sensor activation function, well impact regulating these pathways across various diseases, highlight driving illness.

Language: Английский

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Transcription stress causes an inflammatory response via release of IL-1α

Nature Structural & Molecular Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Language: Английский

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cGAS, an innate dsDNA sensor with multifaceted functions

Cell Insight, Journal Year: 2025, Volume and Issue: unknown, P. 100249 - 100249

Published: April 1, 2025

Language: Английский

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ER-tethering directs TREX1 penetration of a BAF-dependent barrier at micronuclei

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

SUMMARY Micronuclei are membrane-encapsulated nuclear aberrations that form following chromosome segregation errors. Micronuclear membrane collapse permits access of the pattern recognition receptor cGAS and its antagonist, TREX1 exonuclease. carboxy-terminal domain mediated endoplasmic reticulum tethering association is essential for invasion into ruptured micronuclei, however mechanisms underlying this dependency unknown. Here, we identify barrier-to-autointegration assembly factor 1 (BAF) as a key regulator activity at micronuclei. BAF accumulates on micronuclei augments recruitment in manner depends interactions with membrane-associated LEM-domain proteins. Despite delayed entry, exhibits enhanced micronuclear DNA degradation independence from ER-tethering BAF-deficient cells. In accordance, recombinant protein inhibits TREX1-mediated vitro DNA-binding. similarly outcompetes interaction reduces activation These findings reveal, BAF-dependent protective barrier to diffusive entry binding proteins explaining requirement localization suppression productive substrate activate innate immune responses chromosomally unstable

Language: Английский

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Impact of radiation therapy on the immunological tumor microenvironment

Cell chemical biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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MYC controls STING levels to downregulate inflammatory signaling in breast cancer cells upon DNA damage

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108560 - 108560

Published: April 1, 2025

Amplification of the MYC proto-oncogene is frequently observed in various cancer types, including triple negative breast (TNBC). Emerging evidence suggests that suppression local anti-tumor immune responses by MYC, at least part, explains tumor-promoting effects MYC. Specifically, upregulation was demonstrated to suppress tumor-cell intrinsic activation a type I IFN response and thereby hamper innate inflammatory signaling, which may contribute disappointing immunotherapy patients with TNBC. In this study, we show interferes protein expression functionality STING pathway. MYC-mediated downregulation BT-549 MDA-MB-231 triple-negative cell lines require DNA binding ability independent its co-repressor MIZ1. Both STAT1 STAT3 promote steady-state levels STING, cooperates regulating STING. Conversely, affects downstream chemokine production. Furthermore, overexpression hampers triggered damage through etoposide or irradiation treatment, specifically impedes natural killer cells. Collectively, these results controls regulates tumor cell-intrinsic signaling. These our understanding how suppresses signaling TNBC, explain why large fraction TNBC do not benefit from immunotherapy.

Language: Английский

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cGAS-STING DNA-sensing in inflammatory bowel diseases

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

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DNA-sensing pathways in health, autoinflammatory and autoimmune diseases

Nature Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 4, 2024

Language: Английский

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Reduction of chromosomal instability and inflammation is a common aspect of adaptation to aneuploidy

EMBO Reports, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 18, 2024

Abstract Aneuploidy, while detrimental to untransformed cells, is notably prevalent in cancer. Aneuploidy found as an early event during tumorigenesis which indicates that cancer cells have the ability surmount initial stress responses associated with aneuploidy, enabling rapid proliferation despite aberrant karyotypes. To generate more insight into key cellular processes and requirements underlying adaptation we generated a panel of aneuploid clones p53-deficient RPE-1 studied their behavior over time. As expected, de novo-generated initially display reduced fitness, enhanced levels chromosomal instability (CIN), upregulated inflammatory response. Intriguingly, after prolonged culturing, exhibit increased rates maintaining karyotypes, indicative adaptive response state. Interestingly, all adapted CIN signaling, suggesting these are common aspects aneuploidy. Collectively, our data suggests concomitant inflammation require correction allow for fast vitro. Finally, provide evidence amplification oncogenic KRAS can promote adaptation.

Language: Английский

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