HELZ promotes R loop resolution to facilitate DNA double-strand break repair by homologous recombination DOI Open Access
Ramona Haji‐Seyed‐Javadi,

Allyson E. Koyen,

Sandip Kumar Rath

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 15, 2023

Abstract R loops are RNA-DNA hybrid containing structures involved in diverse cellular processes, including DNA double-strand break (DSB) repair. loop homeostasis involving the formation and resolution of is critical for DSB repair, its dysregulation leads to genome instability. Here we show that HELZ helicase promotes facilitate repair by homologous recombination (HR). depletion causes hypersensitivity DSB-inducing agents, localizes binds DSBs. further genomic instability a dependent manner accumulation globally at response DSBs their resolution, thereby facilitating HR promote integrity. Our findings thus define role promoting HR.

Language: Английский

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

Jianing Lin,

Yayun Nan,

Jingyi Sun

et al.

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

Citations

0
HIV-1 Vpr drives epigenetic remodeling to enhance virus transcription and latency reactivation DOI Creative Commons

Nicholas Saladino,

Emily Leavitt,

Hoi Tong Wong

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 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.

Language: Английский

Citations

0
The human HELQ helicase and XRN2 exoribonuclease cooperate in R-loop resolution DOI Creative Commons
Jinming Pan,

H. Betts,

Andrew Cubbon

et al.

Open Biology, Journal Year: 2025, Volume and Issue: 15(2)

Published: Feb. 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.

Language: Английский

Citations

0
Looping forward: exploring R‐loop processing and therapeutic potential DOI Creative Commons
Kalliopi Stratigi, Athanasios Siametis, George A. Garinis

et al.

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

Published: June 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

Language: Английский

Citations

4
Identification of PRMT5 as a therapeutic target in cholangiocarcinoma DOI

Jasmin Elurbide,

Leticia Colyn, M. Ujúe Latasa

et al.

Gut, Journal Year: 2024, Volume and Issue: 74(1), P. 116 - 127

Published: Sept. 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.

Language: Английский

Citations

4
SRSF4-Associated ca-circFOXP1 Regulates Hypoxia-Induced PASMC Proliferation by the Formation of R Loop With Host Gene DOI

Xinyue Song,

Ya Xu, Mengnan Li

et al.

Arteriosclerosis Thrombosis and Vascular Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 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.

Language: Английский

Citations

0
Possible role of human ribonuclease dicer in the regulation of R loops DOI Creative Commons
Klaudia Wójcik, Paulina Krzemińska, Anna Kurzyńska‐Kokorniak

et al.

FEBS Open Bio, Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

Language: Английский

Citations

0
Transcription-Coupled Repair and R-Loop Crosstalk in Genome Stability DOI Open Access

Jeseok Jeon,

Tae‐Hong Kang

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

Citations

0
Advancements and Challenges of R-loops in Cancers: Biological Insights and Future Directions DOI
Dengxiong Li, Fanglin Shao, Xinrui Li

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 610, P. 217359 - 217359

Published: Nov. 27, 2024

Language: Английский

Citations

3
Centromeres in cancer: Unraveling the link between chromosomal instability and tumorigenesis DOI
Mohsen Karami Fath, Ahmad Nazari,

Noushin Parsania

et al.

Medical Oncology, Journal Year: 2024, Volume and Issue: 41(11)

Published: Oct. 1, 2024

Language: Английский

Citations

2