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

The DNA Damage Response and Inflammation in Cancer DOI
Vanessa Klapp, Beatriz Álvarez-Abril, Giuseppe Leuzzi

et al.

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(7), P. 1521 - 1545

Published: April 7, 2023

Genomic stability in normal cells is crucial to avoid oncogenesis. Accordingly, multiple components of the DNA damage response (DDR) operate as bona fide tumor suppressor proteins by preserving genomic stability, eliciting demise with unrepairable lesions, and engaging cell-extrinsic oncosuppression via immunosurveillance. That said, DDR sig-naling can also favor progression resistance therapy. Indeed, signaling cancer has been consistently linked inhibition tumor-targeting immune responses. Here, we discuss complex interactions between inflammation context oncogenesis, progression, Accumulating preclinical clinical evidence indicates that intimately connected emission immunomodulatory signals malignant cells, part a program preserve organismal homeostasis. DDR-driven inflammation, however, have diametrically opposed effects on immunity. Understanding links may unlock novel immunotherapeutic paradigms treat cancer.

Language: Английский

Citations

55
R-loop-dependent promoter-proximal termination ensures genome stability DOI Creative Commons
Congling Xu, Chengyu Li, Jiwei Chen

et al.

Nature, Journal Year: 2023, Volume and Issue: 621(7979), P. 610 - 619

Published: Aug. 9, 2023

Abstract The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions 1,2 . Here we identify a stable association between the genome-stability regulator sensor single-stranded DNA (SOSS) 3 Integrator-PP2A (INTAC) 4–6 Through SSB1-mediated recognition DNA, SOSS–INTAC stimulates promoter-proximal termination attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced instability. SOSS–INTAC-dependent attenuation enhanced by ability SSB1 form liquid-like condensates. Deletion NABP2 (encoding SSB1) or introduction cancer-associated mutations into its intrinsically disordered region leads pervasive accumulation R-loops, highlighting surveillance function that enables timely at promoters constrain R-loop ensure stability.

Language: Английский

Citations

51
Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders DOI Creative Commons
Yige Huang,

Bangyan Liu,

Subhash C. Sinha

et al.

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Nov. 8, 2023

Abstract DNA sensing is a pivotal component of the innate immune system that responsible for detecting mislocalized and triggering downstream inflammatory pathways. Among sensors, cyclic GMP-AMP synthase (cGAS) primary player in cytosolic DNA, including foreign from pathogens self-DNA released during cellular damage, culminating type I interferon (IFN-I) response through stimulator genes (STING) activation. IFN-I cytokines are essential mediating neuroinflammation, which widely observed CNS injury, neurodegeneration, aging, suggesting an upstream role cGAS pathway. In this review, we summarize latest developments on cGAS-STING DNA-driven various neurological diseases conditions. Our review covers current understanding molecular mechanisms activation highlights signaling cell types central peripheral nervous systems, such as resident brain cells, neurons, glial cells. We then discuss different neurodegenerative conditions, tauopathies, Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis, well aging senescence. Finally, lay out advancements research development inhibitors assess prospects targeting STING therapeutic strategies wide spectrum diseases.

Language: Английский

Citations

48
Causes and consequences of DNA single-strand breaks DOI Creative Commons
Keith W. Caldecott

Trends in Biochemical Sciences, Journal Year: 2023, Volume and Issue: 49(1), P. 68 - 78

Published: Nov. 30, 2023

DNA single-strand breaks (SSBs) are among the most common lesions arising in human cells, with tens to hundreds of thousands each cell, day. Cells have efficient mechanisms for sensing and repair these ubiquitous lesions, but failure processes rapidly remove SSBs can lead a variety pathogenic outcomes. The threat posed by unrepaired is illustrated existence at least six genetic diseases which SSB (SSBR) defective, all characterised neurodevelopmental and/or neurodegenerative pathology. Here, I review current understanding how arise impact on critical molecular processes, such as replication gene transcription, their links disease.

Language: Английский

Citations

43
Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer DOI Creative Commons
Takahiko Murayama, Jun Nakayama, Xinpei Jiang

et al.

Cancer Discovery, Journal Year: 2024, Volume and Issue: 14(3), P. 468 - 491

Published: Jan. 4, 2024

Abstract Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as “viral mimicry,” has emerged an effective strategy to convert immunologically “cold” tumors into “hot.” Through curated CRISPR-based screen of RNA helicases, we identified DExD/H-box helicase 9 (DHX9) potent repressor double-stranded (dsRNA) small cell lung cancers (SCLC). Depletion DHX9 induced accumulation dsRNA and triggered tumor-intrinsic immunity. Intriguingly, ablating also aberrant R-loops, which resulted increase DNA damage–derived replication stress SCLCs. In vivo, deletion promoted decrease tumor growth while inducing more immunogenic microenvironment, invigorating responsiveness immune-checkpoint blockade. These findings suggest that is crucial stress, representing promising target for SCLC other genomic instability contributes pathology. Significance: One trigger immune response within enhance immunotherapy efficacy by endogenous “virus-mimetic” accumulation. Here, identify viral-mimicry-inducing factor involved the suppression RNAs R-loops propose novel antitumor See related commentary Chiappinelli, p. 389. This article featured Selected Articles from Issue, 384

Language: Английский

Citations

31
ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity DOI

Matthew B. Maxwell,

Marianne S. Hom, Jawoon Yi

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(13), P. 3390 - 3408.e19

Published: May 15, 2024

Language: Английский

Citations

30
When DNA-damage responses meet innate and adaptive immunity DOI Creative Commons
Jie Tong, Jiangwei Song,

Wuchao Zhang

et al.

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: April 17, 2024

Abstract When cells proliferate, stress on DNA replication or exposure to endogenous external insults frequently results in damage. DNA-Damage Response (DDR) networks are complex signaling pathways used by multicellular organisms prevent Depending the type of broken DNA, various pathways, Base-Excision Repair (BER), Nucleotide Excision (NER), Mismatch (MMR), Homologous Recombination (HR), Non-Homologous End-Joining (NHEJ), Interstrand Crosslink (ICL) repair, and other direct repair can be activated separately combination To preserve homeostasis, innate adaptive immune responses effective defenses against mutation invasion pathogens. It is interesting note that new research keeps showing how closely DDR components system related. immunological response linked effectors such as cyclic GMP-AMP synthase (cGAS)–Stimulator Interferon Genes (STING) pathway. These act sensors damage-caused response. Furthermore, themselves function trigger generation inflammatory cytokines a cascade even programmed cell death. Defective known disrupt genomic stability compromise responses, aggravating imbalance leading serious diseases cancer autoimmune disorders. This study examines most recent developments interaction between elements responses. The network’s modulators’ dual roles may offer perspectives treating infectious disorders damage, including cancer, development target immunotherapy.

Language: Английский

Citations

20
Regulation of cGAS–STING signalling and its diversity of cellular outcomes DOI
Zhengyin Zhang, Conggang Zhang

Nature reviews. Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Language: Английский

Citations

3
Detection of alternative DNA structures and its implications for human disease DOI Creative Commons
Gabriel Matos‐Rodrigues, Julia A. Hisey,

André Nussenzweig

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(20), P. 3622 - 3641

Published: Oct. 1, 2023

Language: Английский

Citations

36
DNA damage and transcription stress DOI Creative Commons
Larissa Milano, Amit Gautam, Keith W. Caldecott

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 84(1), P. 70 - 79

Published: Dec. 15, 2023

Genome damage and transcription are intimately linked. Tens to hundreds of thousands DNA lesions arise in each cell day, many which can directly or indirectly impede transcription. Conversely, the process gene expression is itself a source endogenous as result susceptibility single-stranded damage, conflicts with replication machinery, engagement by cells topoisomerases base excision repair enzymes regulate initiation progression Although such processes tightly regulated normally accurate, on occasion, they become abortive leave behind breaks that drive genome rearrangements, instability, death.

Language: Английский

Citations

34