PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 8, 2024

Abstract R-loops that accumulate at transcription sites pose a persistent threat to genome integrity. PSIP1 is chromatin protein associated with transcriptional elongation complex, possesses histone chaperone activity, and implicated in recruiting RNA processing DNA repair factors sites. Here, we show interacts other proteins involved R-loop homeostasis, including PARP1. Genome-wide mapping of PSIP1, γ-H2AX PSIP1-depleted human mouse cell lines revealed an accumulation damage gene promoters the absence PSIP1. causes local arrest transcription-replication conflict, leading damage. depletion increases 53BP1 foci reduces RAD51 foci, suggesting altered choice. Furthermore, sensitivity cancer cells PARP1 inhibitors DNA-damaging agents induce R-loop-induced These findings provide insights into mechanism through which maintains integrity site transcription.

Язык: Английский

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RNA-DNA triplexes: molecular mechanisms and functional relevance

Trends in Biochemical Sciences, Год журнала: 2024, Номер 49(6), С. 532 - 544

Опубликована: Апрель 5, 2024

Interactions of RNA with DNA are principles gene expression control that have recently gained considerable attention. Among RNA–DNA interactions R-loops and RNA-DNA hybrid G-quadruplexes, as well triplexes. It is proposed triplexes guide RNA-associated regulatory proteins to specific genomic locations, influencing transcription epigenetic decision making. Although triplex formation initially was considered solely an in vitro event, recent progress computational, biochemical, biophysical methods support vivo functionality relevance for control. Here, we review the central methodology biology triplexes, outline paradigms required function, provide examples physiologically important triplex-forming long non-coding RNAs.

Язык: Английский

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Aberrant R-loop–mediated immune evasion, cellular communication, and metabolic reprogramming affect cancer progression: a single-cell analysis

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Янв. 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.

Язык: Английский

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DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Апрель 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

Язык: Английский

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Molecular insights into regulatory RNAs in the cellular machinery

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

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