Neurological Impact of Type I Interferon Dysregulation DOI Creative Commons
Alessio Mylonas

IntechOpen eBooks, Год журнала: 2024, Номер unknown

Опубликована: Июль 31, 2024

Type I interferons are a class of potent and tightly regulated cytokines important for antiviral anti-tumoural innate adaptive immunity. Dysregulated production can have serious neurologic consequences as exemplified in family rare diseases called type interferonopathies. Interferonopathies represent group genetically determined conditions characterised by upregulated interferon causing spectrum neuroinflammatory systemic manifestations. This chapter delves into the historical discovery interferons, their role immunity, subsequent identification interferonopathies placing emphasis on mechanisms dysfunction that often dominate clinical picture. The insights gained from studying these offer valuable lessons neurodegenerative neuropsychiatric which demonstrate considerable overlap with interferonopathies, underscoring broader significance more common diseases. Relevant therapeutic strategies targeting this pathway discussed, emphasising need brain-penetrant approaches.

Язык: Английский

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

Wuchao Zhang

и другие.

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Апрель 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.

Язык: Английский

Процитировано

20
Mechanisms underlining R-loop biology and implications for human disease DOI Creative Commons
Junzhe Liu,

Fengze Li,

Yulong Cao

и другие.

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Фев. 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.

Язык: Английский

Процитировано

1
Advancements and Challenges of R-loops in Cancers: Biological Insights and Future Directions DOI
Dengxiong Li, Fanglin Shao, Xinrui Li

и другие.

Cancer Letters, Год журнала: 2024, Номер 610, С. 217359 - 217359

Опубликована: Ноя. 27, 2024

Язык: Английский

Процитировано

5
DDX41: exploring the roles of a versatile helicase DOI Creative Commons

Lacey Winstone,

Yohan Jung,

Yuliang Wu

и другие.

Biochemical Society Transactions, Год журнала: 2024, Номер 52(1), С. 395 - 405

Опубликована: Фев. 13, 2024

DDX41 is a DEAD-box helicase and conserved across species. Mutations in have been associated with myeloid neoplasms, including myelodysplastic syndrome acute leukemia. Though its pathogenesis not completely known, has shown to many cellular roles, pre-mRNA splicing, innate immune sensing, ribosome biogenesis, translational regulation, R-loop metabolism. In this review, we will summarize the latest understandings regarding various roles of DDX41, as well highlight challenges drug development target DDX41. Overall, understanding molecular mechanisms could help develop novel therapeutic options for mutation-related hematologic malignancies.

Язык: Английский

Процитировано

4
DNA sensors in metabolic and cardiovascular diseases: Molecular mechanisms and therapeutic prospects DOI Creative Commons

Hyosang Kwak,

Ein Lee,

Rajendra Karki

и другие.

Immunological Reviews, Год журнала: 2024, Номер unknown

Опубликована: Авг. 19, 2024

Summary DNA sensors generally initiate innate immune responses through the production of type I interferons. While extensively studied for host defense against invading pathogens, emerging evidence highlights involvement in metabolic and cardiovascular diseases. Elevated levels modified, damaged, or ectopically localized self‐DNA non‐self‐DNA have been observed patients animal models with obesity, diabetes, fatty liver disease, disease. The accumulation cytosolic aberrantly activates signaling pathways, driving pathological progression these disorders. This review roles specific sensors, such as cyclic AMP‐GMP synthase stimulator interferon genes (cGAS‐STING), absent melanoma 2 (AIM2), toll‐like receptor 9 (TLR9), gamma‐inducible protein 16 (IFI16), DNA‐dependent kinase (DNA‐PK), DEAD‐box helicase 41 (DDX41) various We explore how pathways both non‐immune cells contribute to development Furthermore, we discuss intricate interplay between stress responses, offering insights into potential therapeutic targets managing Understanding mechanisms sensor contexts provides a foundation developing novel interventions aimed at mitigating impact pervasive health issues.

Язык: Английский

Процитировано

4
Gain-of-function enhancer variant near KCNB1 causes familial ST-depression syndrome DOI
Alex Hørby Christensen, Gang Pan, Rasmus L. Marvig

и другие.

European Heart Journal, Год журнала: 2025, Номер unknown

Опубликована: Апрель 10, 2025

Abstract Background and Aims Familial ST-depression syndrome (FSTD) is a recently identified inherited cardiac disease associated with arrhythmias systolic dysfunction. The underlying genetic aetiology has remained elusive. This study aimed at finding the causative variant. Methods A total of 67 FSTD patients (20 families) were studied. Linkage analysis whole-genome sequencing (WGS) initially performed. An non-coding variant was functionally characterized in AC16 human cardiomyocytes, muscle tissue, myocardium. In silico analyses, luciferase dCas9-activator/repressor assays, protein–DNA experiments, chromosome conformation capture (4C), RNA also Results electrocardiographic (ECG) phenotype an autosomal dominant manner all families. revealed single peak on 20, WGS single, rare, located 18 kb downstream KCNB1 20 affected individuals. Perfect co-segregation ECG observed together full penetrance creates MEF2-binding site presence allele or MEF2 co-expression enhanced transcriptional activity. assays showed that only gene consistently regulated by locus 4C experiments cells tissue confirmed locus–KCNB1 promoter interaction. Expression endocardial did not document any change expression likely explained expressional heterogeneity. Conclusions gain-of-function enhancer hyperactive regulatory interacts causes FSTD. first time been implicated electrophysiology arrhythmogenesis.

Язык: Английский

Процитировано

0
Multifunctional role of DEAD-box helicase 41 in innate immunity, hematopoiesis and disease DOI Creative Commons
Jing Ma, Susan R. Ross

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Авг. 9, 2024

DEAD-box helicases are multifunctional proteins participating in many aspects of cellular RNA metabolism. helicase 41 (DDX41) particular has pivotal roles innate immune sensing and hematopoietic homeostasis. DDX41 recognizes foreign or self-nucleic acids generated during microbial infection, thereby initiating anti-pathogen responses. also binds to (R)-loops, structures consisting DNA/RNA hybrids a displaced strand DNA that occur transcription, maintaining genome stability by preventing their accumulation. deficiency leads increased R-loop levels, resulting inflammatory responses likely influence stem progenitor cell production development. Beyond nucleic acid binding, associates with involved splicing as well immunity. is tumor suppressor familial sporadic myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML). In the present review, we summarize functions DDX critical biological processes, particularly focusing on DDX41’s association molecules mechanisms underlying its immunity, hematopoiesis development myeloid malignancies.

Язык: Английский

Процитировано

3
DNA-PK and ATM drive phosphorylation signatures that antagonistically regulate cytokine responses to herpesvirus infection or DNA damage DOI Creative Commons
Joshua Justice, Tavis J. Reed,

Brett Phelan

и другие.

Cell Systems, Год журнала: 2024, Номер 15(4), С. 339 - 361.e8

Опубликована: Апрель 1, 2024

Язык: Английский

Процитировано

2
‘From R-lupus to cancer’: Reviewing the role of R-loops in innate immune responses DOI Creative Commons
Leanne Bradley, Kienan I. Savage

DNA repair, Год журнала: 2023, Номер 131, С. 103581 - 103581

Опубликована: Окт. 6, 2023

Cells possess an inherent and evolutionarily conserved ability to detect respond the presence of foreign pathological 'self' nucleic acids. The result is stimulation innate immune responses, signalling host system that defence mechanisms are necessary protect organism. To date, there a vast body literature describing responses various acid species, including dsDNA, ssDNA ssRNA etc., however, limited information available on R-loops. R-loops 3-stranded structures form during transcription, upon DNA damage in other settings. Emerging evidence suggests may also exist for detection R-loop related structures, implicating as drivers inflammatory states. In this review, we aim summarise indicating immunogenic species can trigger physiological settings discuss implications study diseases therapeutic development.

Язык: Английский

Процитировано

6
Protocol for detection of in vitro R-loop formation using dot blots DOI Creative Commons
Jack W. Dowling, Julian R. Smith, Adriana Forero

и другие.

STAR Protocols, Год журнала: 2024, Номер 5(1), С. 102857 - 102857

Опубликована: Янв. 28, 2024

Dot-blot analysis is a technique that allows for fast and convenient detection identification of nucleic acids proteins. Here, we provide guide acid isolation from eukaryotic cells sample processing to detect RNA/DNA hybrids. We then detailed steps quantify dot signal intensity. This protocol can be adapted screening conditions result in the accumulation R-loops. For complete details on use execution this protocol, please refer Smith et al.

Язык: Английский

Процитировано

1