Molecular insights into regulatory RNAs in the cellular machinery DOI Creative Commons
Sumin Yang, Sung-Hyun Kim, Eun-Jeong Yang

и другие.

Experimental & Molecular Medicine, Год журнала: 2024, Номер 56(6), С. 1235 - 1249

Опубликована: Июнь 14, 2024

It is apparent that various functional units within the cellular machinery are derived from RNAs. The evolution of sequencing techniques has resulted in significant insights into approaches for transcriptome studies. Organisms utilize RNA to govern systems, and a heterogeneous class RNAs involved regulatory functions. In particular, increasingly recognized participate intricately functioning across almost all levels biological systems. These systems include those mediating chromatin arrangement, transcription, suborganelle stabilization, posttranscriptional modifications. Any exhibiting activity can be termed typically represented by noncoding RNAs, which constitute substantial portion genome. function based on principle structural changes through cis and/or trans regulation facilitate mutual RNA‒RNA, RNA‒DNA, RNA‒protein interactions. not been clearly elucidated whether identified deep actually anticipated mechanisms. This review addresses dominant properties at layers covers activities, dynamics, modifications, associated molecules, further challenges related therapeutics learning.

Язык: Английский

Non-coding RNAs in disease: from mechanisms to therapeutics DOI
Kinga Németh, Recep Bayraktar, Manuela Ferracin

и другие.

Nature Reviews Genetics, Год журнала: 2023, Номер 25(3), С. 211 - 232

Опубликована: Ноя. 15, 2023

Язык: Английский

Процитировано

327
R-loop-derived cytoplasmic RNA–DNA hybrids activate an immune response DOI
Magdalena P. Crossley,

Chenlin Song,

M Bocek

и другие.

Nature, Год журнала: 2022, Номер 613(7942), С. 187 - 194

Опубликована: Дек. 21, 2022

Язык: Английский

Процитировано

162
Mechanisms of immune checkpoint inhibitors: insights into the regulation of circular RNAS involved in cancer hallmarks DOI Creative Commons
Lingjiao Meng,

Haotian Wu,

Jiaxiang Wu

и другие.

Cell Death and Disease, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 4, 2024

Abstract Current treatment strategies for cancer, especially advanced are limited and unsatisfactory. One of the most substantial advances in cancer therapy, last decades, was discovery a new layer immunotherapy approach, immune checkpoint inhibitors (ICIs), which can specifically activate cells by targeting checkpoints. Immune checkpoints type immunosuppressive molecules expressed on cells, regulate degree activation avoid autoimmune responses. ICIs, such as anti-PD-1/PD-L1 drugs, has shown inspiring efficacy broad applicability across various cancers. Unfortunately, not all patients benefit remarkably from overall response rates to ICIs remain relatively low types. Moreover, primary acquired resistance pose serious challenges clinical application immunotherapy. Thus, deeper understanding molecular biological properties regulatory mechanisms is urgently needed improve options fo r current therapies. Recently, circular RNAs (circRNAs) have attracted increasing attention, only due their involvement aspects hallmarks, but also impact shaping tumor microenvironment. In this review, we systematically summarize status existing roles circRNAs Meanwhile, aim settle issue an evidence-oriented manner that involved hallmarks effects

Язык: Английский

Процитировано

57
G-quadruplexes associated with R-loops promote CTCF binding DOI Creative Commons
Phillip Wulfridge, Qingqing Yan,

Nathaniel Rell

и другие.

Molecular Cell, Год журнала: 2023, Номер 83(17), С. 3064 - 3079.e5

Опубликована: Авг. 7, 2023

Язык: Английский

Процитировано

55
Causes and consequences of DNA single-strand breaks DOI Creative Commons
Keith W. Caldecott

Trends in Biochemical Sciences, Год журнала: 2023, Номер 49(1), С. 68 - 78

Опубликована: Ноя. 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.

Язык: Английский

Процитировано

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

и другие.

Cancer Discovery, Год журнала: 2024, Номер 14(3), С. 468 - 491

Опубликована: Янв. 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

Язык: Английский

Процитировано

31
The ARID1A-METTL3-m6A axis ensures effective RNase H1-mediated resolution of R-loops and genome stability DOI Creative Commons
Jun Zhang, Feng Chen, Ming Tang

и другие.

Cell Reports, Год журнала: 2024, Номер 43(2), С. 113779 - 113779

Опубликована: Фев. 1, 2024

R-loops are three-stranded structures that can pose threats to genome stability. RNase H1 precisely recognizes drive their resolution within the genome, but underlying mechanism is unclear. Here, we report ARID1A with high affinity in an ATM-dependent manner. recruits METTL3 and METTL14 R-loop, leading m6A methylation of R-loop RNA. This modification facilitates recruitment driving its promoting DNA end resection at DSBs, thereby ensuring Depletion ARID1A, METTL3, or leads accumulation reduced cell survival upon exposure cytotoxic agents. Therefore, function a coordinated, temporal order DSB sites recruit ensure efficient resolution. Given association levels resistance genotoxic therapies patients, these findings open avenues for exploring potential therapeutic strategies cancers abnormalities.

Язык: Английский

Процитировано

21
Intertwining roles of R-loops and G-quadruplexes in DNA repair, transcription and genome organization DOI
Phillip Wulfridge,

Kavitha Sarma

Nature Cell Biology, Год журнала: 2024, Номер 26(7), С. 1025 - 1036

Опубликована: Июнь 24, 2024

Язык: Английский

Процитировано

16
APOBEC3A deaminates CTG hairpin loops to promote fragility and instability of expanded CAG/CTG repeats DOI Creative Commons
Rebecca E. Brown,

Margo Coxon,

Bianca Larsen

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(2)

Опубликована: Янв. 7, 2025

CAG/CTG repeats are prone to expansion, causing several inherited human diseases. The initiating sources of DNA damage which lead inaccurate repair the repeat tract cause expansions not fully understood. Expansion-prone actively transcribed and forming stable R-loops with hairpin structures on displaced single-stranded (S-loops). We previously determined that by Saccharomyces cerevisiae cytosine deaminase, Fcy1, was required for both fragility instability tracts engaged in R-loops. To determine whether this mechanism is more universal, we expressed cytidine deaminases APOBEC3A (A3A), APOBEC3B (A3B), or activation-induced deaminase (AID) our yeast system. show mutagenic activity Apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptides causes instability, A3A having greatest effect followed A3B least from AID. A3A-induced exacerbated enrichment at site. A3B-induced dependent MutLγ nuclease a lesser extent, base excision factors. Deaminase assays substrates containing CTG GTC triplet sequences revealed prefers cytidines within loop, bulges stem alter preferred locations. Analysis RNA expression levels cortex samples brain tissue exhibits its elevated Huntington’s disease (HD) patient samples. These results implicate deamination as potential source HD other expansion disorders.

Язык: Английский

Процитировано

2
Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor DOI Creative Commons
Zdenka Hašanová, Veronika Klapstova, Odil Porrúa

и другие.

Nucleic Acids Research, Год журнала: 2023, Номер 51(6), С. 2818 - 2837

Опубликована: Март 2, 2023

Abstract Prolonged pausing of the transcription machinery may lead to formation three-stranded nucleic acid structures, called R-loops, typically resulting from annealing nascent RNA with template DNA. Unscheduled persistence R-loops and polymerases interfere itself other essential processes such as DNA replication repair. Senataxin (SETX) is a putative helicase, mutated in two neurodegenerative disorders, which has been implicated control R-loop accumulation termination. However, understanding precise role SETX these precluded by absence direct characterisation biochemical activities. Here, we purify characterise helicase domain parallel its yeast orthologue, Sen1. Importantly, show that bona fide ability resolve R-loops. Furthermore, retained termination activity Sen1 but functions species-specific manner. Finally, subsequent variants harbouring disease-associated mutations shed light into effect on folding properties. Altogether, results broaden our function gene expression maintenance genome integrity provide clues elucidate molecular basis SETX-associated diseases.

Язык: Английский

Процитировано

40