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

Inflammation, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 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

Language: Английский

---

Transcription: friend or foe of genome stability

FEBS Letters, Journal Year: 2025, Volume and Issue: 599(2), P. 143 - 146

Published: Jan. 1, 2025

Language: Английский

---

SRSF2 overexpression induces transcription-/replication-dependent DNA double-strand breaks and interferes with DNA repair pathways to promote lung tumor progression

NAR Cancer, Journal Year: 2025, Volume and Issue: 7(2)

Published: April 2, 2025

Abstract SRSF2 (serine/arginine-rich splicing factor 2) is a critical regulator of pre-messenger RNA splicing, which also plays noncanonical functions in transcription initiation and elongation. Although elevated levels are associated with advanced stages lung adenocarcinoma (LUAD), the mechanisms connecting to tumor progression remain unknown. We show that overexpression increases global replicative stress LUAD cells, correlates production DNA damage, notably double-strand breaks (DSBs), likely resulting from conflicts between replication. Moreover, regulates repair pathways by promoting homologous recombination inhibiting nonhomologous end joining. Mechanistically, interacts enhances MRE11 (meiotic 11) recruitment chromatin, while downregulating 53BP1 messenger protein levels. Both events contributing SRSF2-mediated process rerouting. Lastly, we expression commonly predicts poor outcome patients. Altogether, our results identify mechanism promotes cancer through fine control both DSB repair. Finally, knockdown impairs late ionizing radiation-induced DSBs, suggesting more function recombination.

Language: Английский

---

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

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3744 - 3744

Published: April 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.

Language: Английский

---

Transcription as a double‐edged sword in genome maintenance

FEBS Letters, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

Genome maintenance is essential for the integrity of genetic blueprint, which only a small fraction transcribed in higher eukaryotes. DNA lesions occurring genome trigger transcription pausing and transcription‐coupled repair. There are two major repair pathways. The nucleotide excision (TC‐NER) pathway has been well studied decades, while homologous recombination (TC‐HR) recently gained attention. Importantly, recent studies have uncovered crucial roles RNA transcripts TC‐HR, opening exciting directions future research. Transcription also plays pivotal regulating stability highly specialized genomic structures such as telomeres, centromeres, fragile sites. Despite their positive function maintenance, can be sources instability, especially when colliding with replication forming unscheduled pathological RNA:DNA hybrids (R‐loops), respectively. Pathological R‐loops result from transcriptional stress, may induced by dysregulation. Future investigation into interplay between will reveal novel molecular bases stress‐associated providing therapeutic targets human disease intervention.

Language: Английский

---