Identification and Construction of a R-loop Mediated Diagnostic Model and Associated Immune Microenvironment of COPD through Machine Learning and Single-Cell Transcriptomics

Inflammation, Год журнала: 2025, Номер unknown

Опубликована: Янв. 11, 2025

Chronic obstructive pulmonary disease (COPD) is a prevalent chronic inflammatory airway with high incidence and significant burden. R-loops, functional chromatin structure formed during transcription, are closely associated inflammation due to its aberrant formation. However, the role of R-loop regulators (RLRs) in COPD remains unclear. Utilizing both bulk transcriptome data single-cell RNA sequencing data, we assessed diverse expression patterns RLRs lung tissues patients. A lower score was found patients neutrophils. 12 machine learning algorithms (150 combinations) identified 14 hub (CBX8, EHD4, HDLBP, KDM6B, NFAT5, NLRP3, NUP214, PAFAH1B3, PINX1, PLD1, POLB, RCC2, RNF213, VIM) COPD. RiskScore based on two distinct subtypes. Patient groups at risk (low scores) had higher immune increase neutrophils their microenvironment compared low-risk groups. PD-0325901 QL-X-138 represent prospective treatments for high-risk score) (high Finally, RT-PCR experiments confirmed differences 8 (EHD4, mice tissue. R-loops significantly contribute development constructing predictive models may provide crucial insight into personalized treatment strategies

Язык: Английский

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HIV-1 Vpr drives epigenetic remodeling to enhance virus transcription and latency reactivation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 31, 2025

Abstract Despite decades of research, the primary proviral function HIV-1 Vpr accessory protein remains enigmatic. is essential for pathogenesis in vivo and virus replication myeloid cells, but underlying cause-and-effect mechanism(s) driving these phenomena are poorly understood. Canonically, hijacks a cellular ubiquitin ligase complex to target several dozen host proteins proteasomal degradation. Many substrates were recently revealed be involved DNA damage repair (DDR), which rationalizes longstanding observation that induces constitutive activation DDR signaling. Here, we use combination functional, biochemical, genetic approaches establish clear mechanistic link between Vpr-induced signaling remodeling epigenetic landscape enhance promoter activity during acute infection reactivation from latency. Functional, genetic, bimolecular fluorescence complementation experiments reveal utilizes degradation-dependent -independent mechanisms induce segregates into two discrete pools with dedicated activities—A multimeric pool nucleus associated chromatin monomeric DCAF1 cytoplasm. nuclear environment present common subtypes worldwide provides rationale its essentiality replication. Author summary While plays an role replication, molecular remain Vpr’s best characterized ability depletion by hijacking E3-ubiquitin complex. promotes global We demonstrate linked signaling, it occurs through both mechanisms. Moreover, this circulating globally. This study novel insights how exploits pathways sheds light on function.

Язык: Английский

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The human HELQ helicase and XRN2 exoribonuclease cooperate in R-loop resolution

Open Biology, Год журнала: 2025, Номер 15(2)

Опубликована: Фев. 1, 2025

The human HELQ helicase is a superfamily 2, 3′-5 homologous to POLQ and RNA helicases of the Ski2-like subfamily. It involved in diverse aspects DNA repair an emerging prognosis biomarker novel drug target for cancer therapy. interacts with RPA through its inherently disordered N-HELQ domain hence recruited RPA-bound substrates. Our study reveals role R-loop resolution. We show cells vitro that by at R-loops, which are then resolved if catalytically active as ATPase/helicase. Furthermore, we identify functional interaction XRN2, nuclear 5′ 3′ exoribonuclease, suggest coordinates unwinding digestion XRN2. Collectively, assign new biological function genome stability metazoans involvement XRN2 metabolism.

Язык: Английский

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Looping forward: exploring R‐loop processing and therapeutic potential

FEBS Letters, Год журнала: 2024, Номер unknown

Опубликована: Июнь 6, 2024

Recently, there has been increasing interest in the complex relationship between transcription and genome stability, with specific attention directed toward physiological significance of molecular structures known as R‐loops. These arise when an RNA strand invades into DNA duplex, their formation is involved a wide range regulatory functions affecting gene expression, repair processes or cell homeostasis. The persistent presence R‐loops, if not effectively removed, contributes to instability, underscoring factors responsible for resolution modification. In this review, we provide comprehensive overview how R‐loop processing can drive either beneficial harmful outcome. Additionally, explore potential manipulating such devise rationalized therapeutic strategies targeting aberrant accumulation

Язык: Английский

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Identification of PRMT5 as a therapeutic target in cholangiocarcinoma

Gut, Год журнала: 2024, Номер 74(1), С. 116 - 127

Опубликована: Сен. 11, 2024

Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors limited. Therefore, new therapeutic strategies need be identified.

Язык: Английский

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SRSF4-Associated ca-circFOXP1 Regulates Hypoxia-Induced PASMC Proliferation by the Formation of R Loop With Host Gene

Arteriosclerosis Thrombosis and Vascular Biology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

BACKGROUND: Pulmonary hypertension (PH) is a rare and fatal disease, the pathological changes of which include pulmonary arterial smooth muscle cell (PASMC) proliferation, basis vascular remodeling. Studies have demonstrated that chromatin-associated circRNA can regulate variety biological processes, including PASMC proliferation in patients with hypoxic PH. However, role PH remains largely unexplored. In this study, we aimed to identify function mechanism METHODS: The ca-circFOXP1 was investigated mouse PASMCs SuHX (Sugen5416+hypoxia) model mice through use antisense oligonucleotide knockdown adeno-associated virus–mediated knockdown. Through bioinformatic sequence alignment, chromatin isolation by RNA purification, Cell Counting Kit 8, 5-ethynyl-2-deoxyuridine, Western blot, other experiments, were verified. RESULTS: expression found be significantly increased PASMCs. Moreover, level host protein FOXP1 (forkhead box 1) R loop, thereby influencing phosphorylation activity SMAD2 (SMAD family member 2) and, consequently, It noteworthy m6A modification promote formation loop between gene , regulating protein. Furthermore, identified splicing factor SRSF4 (serine/arginine rich 4) upregulate exons 6 9 pre-mRNA. CONCLUSIONS: results upregulated ca-circFOXP1, methylation promoted R-loop genes, regulated FOXP1, then affected SMAD2, mediating leading These provide theoretical for further study mechanisms may certain insights.

Язык: Английский

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Possible role of human ribonuclease dicer in the regulation of R loops

FEBS Open Bio, Год журнала: 2025, Номер unknown

Опубликована: Март 24, 2025

R loops are three-stranded nucleic acid structures that form naturally in cells under various conditions, mainly as intermediates during replication or by-products transcription. involved the regulation of many important cellular processes, including replication, transcription, centromere stabilization, protection chromosome ends, control telomere length. Unscheduled linked to diseases, cancer, neurodegenerative, inflammatory disorders. The list cancer diseases excessive loop accumulation is growing rapidly. There currently much debate about understanding abnormal formation and its impact on genome instability development. In this review, we briefly describe nature loops, their physiological pathological proteins loops. addition, emphasize possible role human ribonuclease Dicer, a multi-tasking protein mostly known for microRNA biogenesis, We also discuss involvement development potential use diagnostic biomarkers. Knowledge molecular mechanisms underlying dysregulation may significantly improve our biology provide new directions research.

Язык: Английский

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Transcription-Coupled Repair and R-Loop Crosstalk in Genome Stability

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(8), С. 3744 - 3744

Опубликована: Апрель 16, 2025

Transcription-coupled repair (TCR) and R-loops are two interrelated processes critical to the maintenance of genome stability during transcription. TCR, a specialized sub-pathway nucleotide excision repair, rapidly removes transcription-blocking lesions from transcribed strand active genes, thereby safeguarding transcription fidelity cellular homeostasis. In contrast, R-loops, RNA–DNA hybrid structures formed co-transcriptionally, play not only regulatory roles in gene expression replication but can also contribute instability when persistently accumulated. Recent experimental evidence has revealed dynamic crosstalk between TCR R-loop resolution pathways. This review highlights current molecular insights into biology, discusses impact their crosstalk, explores emerging therapeutic strategies aimed at optimizing DNA reducing disease risk conditions such as cancer neurodegenerative disorders.

Язык: Английский

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Advancements and Challenges of R-loops in Cancers: Biological Insights and Future Directions

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

Опубликована: Ноя. 27, 2024

Язык: Английский

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Centromeres in cancer: Unraveling the link between chromosomal instability and tumorigenesis

Medical Oncology, Год журнала: 2024, Номер 41(11)

Опубликована: Окт. 1, 2024

Язык: Английский

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