AKT1 interacts with DHX9 to Mitigate R Loop–Induced Replication Stress in Ovarian Cancer DOI
Tzu‐Ting Huang, Chih-Yuan Chiang, Jayakumar R. Nair

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(6), P. 887 - 904

Published: Jan. 19, 2024

Abstract PARP inhibitor (PARPi)–resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed quantitative high-throughput drug combination screen that identified the of an ATR (ATRi) and AKT (AKTi) as effective treatment strategy for both PARPi-sensitive PARPi-resistant BRCAm HGSOC. The ATRi AKTi induced DNA damage R loop–mediated replication stress (RS). Mechanistically, kinase domain AKT1 directly interacted DHX9 facilitated recruitment to loops. increased ATRi-induced RS by mitigating Moreover, was upregulated in tumors from patients HGSOC, high coexpression correlated worse survival. Together, this study reveals interaction between facilitates loop resolution identifies combining rational HGSOC irrespective PARPi resistance status. Significance: Inhibition pathways cooperatively induces loop–associated cancer, providing rationale support development combinations. See related commentary Ramanarayanan Oberdoerffer, p. 793

Language: Английский

LINE-1 retrotransposition and its deregulation in cancers: implications for therapeutic opportunities DOI Open Access
Carlos Mendez‐Dorantes, Kathleen H. Burns

Genes & Development, Journal Year: 2023, Volume and Issue: 37(21-24), P. 948 - 967

Published: Nov. 1, 2023

Long interspersed element 1 (LINE-1) is the only protein-coding transposon that active in humans. LINE-1 propagates genome using RNA intermediates via retrotransposition. This activity has resulted sequences occupying approximately one-fifth of our genome. Although most copies are immobile, ∼100 retrotransposition-competent. Retrotransposition normally limited epigenetic silencing, DNA repair, and other host defense mechanisms. In contrast, overexpression retrotransposition hallmarks cancers. Here, we review mechanisms regulation how may promote genetic heterogeneity tumors. Finally, discuss therapeutic strategies to exploit biology

Language: Английский

Citations

27
Organic‐Platinum Hybrids for Covalent Binding of G‐Quadruplexes: Structural Basis and Application to Cancer Immunotherapy DOI
Liu‐Yi Liu,

Tianzhu Ma,

You‐Liang Zeng

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(36)

Published: July 19, 2023

G-quadruplexes (G4s) have been revived as promising therapeutic targets with the development of immunotherapy, but G4-mediated immune response remains unclear. We designed a novel class G4-binding organic-platinum hybrids, L1 -cispt and -transpt, spatial matching for G4 binding DNA reactivity site locking. The solution structure -transpt-MYT1L demonstrated effectiveness covalent revealed binding-guided dynamic balance, accompanied by destruction A5-T17 base pairs to achieve platinum unit N7 G6 residue. Furthermore, -cispt- -transpt-mediated genomic dysfunction could activate retinoic acid-induced gene I (RIG-I) pathway induce immunogenic cell death (ICD). use -cispt/L1 -transpt-treated dying cells vaccines stimulated robust effectively inhibited tumor growth in vivo. Our findings highlight importance rational combination specific recognition locking G4-trageting drug design their potential immunotherapy.

Language: Английский

Citations

26
Microglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage DOI
Ermioni S. Arvanitaki, Evi Goulielmaki, Katerina Gkirtzimanaki

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(17)

Published: April 18, 2024

DNA damage and neurodegenerative disorders are intimately linked but the underlying mechanism remains elusive. Here, we show that persistent lesions in tissue-resident macrophages carrying an XPF-ERCC1 repair defect trigger neuroinflammation neuronal cell death mice. We find microglia accumulate dsDNAs chromatin fragments cytosol, which sensed thereby stimulating a viral-like immune response

Language: Английский

Citations

12
R-loop and diseases: the cell cycle matters DOI Creative Commons
Yuqin Xu,

Yue Jiao,

Chengbin Liu

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: April 27, 2024

Abstract The cell cycle is a crucial biological process that involved in growth, development, and reproduction. It can be divided into G1, S, G2, M phases, each period closely regulated to ensure the production of two similar daughter cells with same genetic material. However, many obstacles influence cycle, including R-loop formed throughout this process. triple-stranded structure, composed an RNA: DNA hybrid single strand, which ubiquitous organisms from bacteria mammals. existence has important significance for regulation various physiological processes. aberrant accumulation due its limited resolving ability will detrimental cells. For example, damage genomic instability, caused by R-loop, activate checkpoints turn induce arrest death. At present, growing number factors have been proven prevent or eliminate thereby avoiding mutations. Therefore, we need gain detailed insight resolution at different stages cycle. In review, review current knowledge play role as well how mutations these lead onset progression diseases.

Language: Английский

Citations

12
Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint DOI Creative Commons

Rachel Mardjuki,

Songnan Wang,

Jacqueline A. Carozza

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(5), P. 114209 - 114209

Published: May 1, 2024

2'3'-Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) is a second messenger synthesized upon detection of cytosolic double-stranded DNA (dsDNA) and passed between cells to facilitate downstream immune signaling. Ectonucleotide pyrophosphatase phosphodiesterase I (ENPP1), an extracellular enzyme, was the only metazoan hydrolase known regulate cGAMP levels dampen anti-cancer immunity. Here, we uncover ENPP3 as likely other under homeostatic conditions. has tissue expression pattern distinct from ENPP1's accounts for all hydrolysis activity in ENPP1-deficient mice. Importantly, also show that, with ENPP1, selectively abolishing ENPP3's results diminished cancer growth metastasis certain tumor types stimulator interferon genes (STING)-dependent manner. Both ENPP1 are enzymes, suggesting dominant role that must play mediator cell-cell innate communication. Our work demonstrates non-redundantly cGAMP-STING signaling, pointing target immunotherapy.

Language: Английский

Citations

10
Aberrant R-loop–mediated immune evasion, cellular communication, and metabolic reprogramming affect cancer progression: a single-cell analysis DOI Creative Commons
Shichao Zhang, Yang Liu, Yichi Sun

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Jan. 10, 2024

Abstract Dysregulation of R-loop homeostasis is closely related to various human diseases, including cancer. However, the causality aberrant R-loops in tumor progression remains unclear. In this study, using single-cell RNA-sequencing datasets from lung adenocarcinoma (LUAD), we constructed an scoring model characterize state according identified regulators EGFR mutations, tissue origins, and TNM stage. We then evaluated relationships score with microenvironment (TME) treatment response. Furthermore, potential roles FANCI-mediated LUAD were explored a series vitro experiments. Results showed that malignant cells low scores displayed glycolysis epithelial–mesenchymal transition pathway activation immune escape promotion, thereby hampering antitumor therapeutic effects. Cell communication analysis suggested contributed T cell exhaustion. subsequently validated prognostic value by bulk transcriptome across 33 types. The well predicted patients’ response targeted therapy, chemotherapy, or immunotherapy 32 independent cohorts. Remarkably, changes distribution mediated FANCI deficiency blocked activity Ras signaling pathway, suppressing tumor-cell proliferation dissemination. conclusion, study reveals underlying molecular mechanism metabolic reprogramming exhaustion under patterns, resulting progression. Therefore, incorporating anticancer methods based on into schemes precision medicine may be beneficial.

Language: Английский

Citations

9
DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells DOI Creative Commons
Xingxing Ren,

Qiuyuan Liu,

Peirong Zhou

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 9, 2024

Abstract Epithelial barrier dysfunction and crypt destruction are hallmarks of inflammatory bowel disease (IBD). Intestinal stem cells (ISCs) residing in the crypts play a crucial role continuous self-renewal rapid recovery intestinal epithelial (IECs). However, how ISCs dysregulated IBD remains poorly understood. Here, we observe reduced DHX9 protein levels patients, mice with conditional depletion epithelium ( Dhx9 ΔIEC ) exhibit an increased susceptibility to experimental colitis. Notably, display significant reduction numbers Paneth cells. Further investigation using ISC-specific or cell-specific -deficient demonstrates involvement ISC-expressed maintaining homeostasis. Mechanistically, deficiency leads abnormal R-loop accumulation, resulting genomic instability cGAS-STING-mediated response, which together impair ISC function contribute pathogenesis IBD. Collectively, our findings highlight R-loop-mediated as risk factor

Language: Английский

Citations

9
TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival DOI Creative Commons
Pauline Lascaux, Gwendoline Hoslett,

Sara Tribble

et al.

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

Citations

9
Mechanisms underlining R-loop biology and implications for human disease DOI Creative Commons
Junzhe Liu,

Fengze Li,

Yulong Cao

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 21, 2025

R-loops are three-stranded non-canonical nucleic acid structures composed of nascent RNA hybridized with the template DNA strand, leaving non-template strand displaced. These play crucial roles in regulating gene expression, replication, and transcription processes. However, have also been increasingly described as highly deleterious, causing genomic instability damage. To maintain at a relatively safe level, complex regulatory mechanisms exist to prevent their excessive formation. The growing understanding R-loop functions has provided valuable insights into structure potential clinical applications. Emerging research indicates that contribute pathogenesis various disorders, including neurodegenerative, immune-related, neoplastic diseases. This review summarizes metabolism its significance etiology associated disorders. By elucidating governing R-loops, we aim establish theoretical foundation for disease exploring novel therapeutic strategies targeting these hybrid structures.

Language: Английский

Citations

1
The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer’s disease DOI Creative Commons

Shuiyue Quan,

Xiaofeng Fu,

Huimin Cai

et al.

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 4, 2025

The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing damage-associated molecular patterns (DAMPs), inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation this pathway culminates in AD-related neuroinflammation neurodegeneration. A substantial body mitochondria are involved critical pathogenic mechanisms AD, whose damage leads release mitochondrial (mtDNA) into extramitochondrial space. This leaked mtDNA serves DAMP, various pattern recognition receptors defense networks brain, including cGAS-STING pathway, ultimately leading an imbalance homeostasis. Therefore, modulation mtDNA-cGAS-STING restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In review, we focus on during stress activation pathway. Additionally, delve research progress further discuss primary directions potential hurdles developing targeted therapeutic drugs, gain deeper understanding pathogenesis provide new approaches its therapy.

Language: Английский

Citations

1