PLK1 Phosphorylates WRN at Replication Forks DOI
Lei Wang, Daheng He,

Qianjin Li

et al.

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2024, Volume and Issue: 392(2), P. 100051 - 100051

Published: Nov. 30, 2024

Prostate cancer, particularly castration-resistant prostate remains a serious public health issue. Androgen signaling inhibitors have emerged as major treatment approach but with limited success. Thus, identification of novel targets is high clinical relevance. Polo-like kinase 1 (PLK1) has documented roles in various aspects including resistance to androgen inhibitors. Radiotherapy another for treating how Plk1 might regulate the efficacy radiotherapy unknown. Nonhomologous end joining (NHEJ) and homologous recombination (HR) are 2 DNA repair pathways, cellular choices between NHEJ HR being elegantly regulated by end-processing. However, long-range resection poorly understood. It been that Werner syndrome protein (WRN) actively involved pathway. In this study, we demonstrate PLK1-associated phosphorylation WRN regulates at double-strand breaks, thereby promoting chromosome stability. Cells expressing nonphosphorylatable mutant show phenotype similar null cells because they lack ability increase NHEJ. summary, reveal Mre11, Rad50 Nbs1 promotes resection, eventually affecting break pathways. SIGNIFICANCE STATEMENT: Both damage PLK1 play critical cancer. The data presented here will provide guidance on manipulate improve settings.

Language: Английский

Design and synthesis of quinazolin-4-one derivatives as potential anticancer agents and investigation of their interaction with RecQ helicases DOI

Hanan S. Haggag,

Shaimaa M. Aboukhatwa, Mohamed S. Nafie

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 144, P. 107086 - 107086

Published: Jan. 4, 2024

Language: Английский

Citations

4
Biophysical investigation of the molecular interaction between minichromosome maintenance protein 6 and Bloom syndrome helicase DOI Creative Commons
Min June Yang, Haeun Lee,

Donguk Kang

et al.

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

Published: Feb. 25, 2025

The minichromosome maintenance protein (MCM) complex and Bloom syndrome helicase (BLM) are crucial components in DNA replication cell division. MCM, a hexameric that unwinds double‐stranded DNA, serves as an important diagnostic prognostic biomarker for cancer cells target anticancer drug development. BLM, associated with G‐quadruplex structures, is another key maintaining genomic stability. In this study, we investigate the interaction between MCM6 BLM at atomic level, their expression levels highly correlated various types, elevated indicating poor prognosis. To elucidate molecular basis of MCM6/BLM interaction, employed fluorescence polarization anisotropy analysis, NMR chemical shifts perturbation analysis (CSP), paramagnetic relaxation enhancement (PRE) experiments. binding domain (MBD) C D exhibit similar affinities to winged‐helix (WHD). However, significant CSPs MBD‐D PRE experiments suggested closer WHD than MBD‐C. Despite both proteins containing numerous negatively charged residues, hydrophobic interactions govern association MBD‐D. This biophysical characterization provides new insights into functional relationship challenges existing models. Our findings reveal binds different site its other known partner chromatin licensing factor. Understanding these protein–protein level may contribute development novel therapies targeting interaction.

Language: Английский

Citations

0
Werner helicase as a therapeutic target in mismatch repair deficient colorectal cancer DOI

Suisui Hao,

Zhaojin Liu, Heinz‐Josef Lenz

et al.

DNA repair, Journal Year: 2025, Volume and Issue: unknown, P. 103831 - 103831

Published: April 1, 2025

Language: Английский

Citations

0
Regulation of pathway choice in DNA repair after Double-strand Breaks DOI

Nitu Kumari,

Ekjot Kaur, Sathees C. Raghavan

et al.

Current Opinion in Pharmacology, Journal Year: 2024, Volume and Issue: 80, P. 102496 - 102496

Published: Dec. 9, 2024

Language: Английский

Citations

3
Specific Monitoring the DNA Helicase Function via Anchor‐Embedded DNA Probe DOI Creative Commons

Keni Ning,

Xiaoyan Tang, Zhe Li

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 31, 2024

DNA helicases play a pivotal role in maintaining genome integrity by unwinding the double helix and are often considered promising targets for drug development. However, assessing specific helicase activity living cells remains challenging. Herein, first anchor-embedded duplex (ATED) probe, 17GC, is constructed to uniquely monitor of Werner syndrome (WRN), clinical anticancer target. This probe integrates biophysical screening molecular simulation approaches. The 17GC consists two components: one bubble structure as an anchor recruiting WRN cells, second GC-rich helices on both ends bubble, which allow high sensitivity detecting activity. In vitro evaluations demonstrate that highly sensitive (LOD = 33.5 pm) compared wide range other enzymes, including nucleases. Cellular evaluation reveals ATED exhibits remarkable performance monitoring inhibitory efficiency inhibitors various cell types. study introduces novel approach designing probes holds promise biological characterization

Language: Английский

Citations

2
BLM promotes malignancy in PCa by inducing KRAS expression and RhoA suppression via its interaction with HDGF and activation of MAPK/ERK pathway DOI

Yingchu Guo,

Houqiang Xu,

Mengqiu Huang

et al.

Journal of Cell Communication and Signaling, Journal Year: 2022, Volume and Issue: 17(3), P. 757 - 772

Published: Dec. 27, 2022

Language: Английский

Citations

9
Case report: A novel mutation of RecQ-like helicase 5 in a Chinese family with early myocardial infarction, coronary artery disease, and stroke hemiplegia DOI Creative Commons
Yi Tang, Qian Wang,

Wei-Kai Zhang

et al.

Frontiers in Genetics, Journal Year: 2023, Volume and Issue: 14

Published: April 26, 2023

Background: Myocardial infarction (MI) is a type of severe coronary artery disease (CAD) that can lead to heart failure and sudden cardiac death. The prevalence globally estimated at 1%-2%, which ∼60% cases are the consequence MI as primary cause. At present, several disease-causing genes have been identified may be responsible for MI, such autophagy-related 16-like 1 (ATG16L1) RecQ-like helicase 5 (RECQL5). Methods: In this study, we enrolled Chinese family with CAD, stroke hemiplegia. Whole-exome sequencing was applied analyze genetic lesion proband. Sanger used validate candidate mutation in five members 200 local control cohorts. Results: After data filtering, detected novel (NM_004259: c.1247T>C/p.I416T) RECQL5 further validated existent affected individuals, including proband's younger sister her mother, absent other healthy Furthermore, bioinformatics analysis confirmed mutation, located highly evolutionarily conserved site, predicted deleterious change hydrophobic surface area aliphatic index RECQL5. Conclusion: Here, report second underlying CAD by whole-exome sequencing. Our study expanded spectrum mutations contributed diagnosis counseling CAD.

Language: Английский

Citations

2
The Expression Characteristics and Function of the RECQ Family in Pan-Cancer DOI Creative Commons
Yuanyuan Zhou,

Xucheng Huang,

Liya Wang

et al.

Biomedicines, Journal Year: 2023, Volume and Issue: 11(8), P. 2318 - 2318

Published: Aug. 21, 2023

Background: The genes of the RECQ DNA helicase family play a part in preserving stability genome and controlling different disease mechanisms. However, expression features RECQs relation to pan-cancer, their correlation with immune microenvironment tumors, landscape prognostic power are still undisclosed. Methods: Various sequence clinical data extracted from 33 cancers were utilized generate comprehensive overview landscape. Afterward, we discovered variations gene expression, potential enrichment functions, genetic alterations, analysis related response tumors. Additionally, explored characteristics diagnostic significance RECQs. And important association RECQL4 liver hepatocellular carcinoma (LIHC) was investigated. Results: exhibited extensive mutations types cancers. may be influenced by an oncogenic mutation certain cancer, resulting observed genomic epigenetic changes diverse tumor formations. Furthermore, originating tumors significant tumor, indicating as promising targets for therapy. Patient prognosis significantly associated majority family. In LIHC, eventually emerged separate determinant. Conclusions: To summarize, essential regulation system serves indicator LIHC. results our study offer fresh perspectives on bioinformatics perspective emphasize importance diagnosis treatment cancer.

Language: Английский

Citations

2
Widespread genomic/molecular alterations of DNA helicases and their clinical/therapeutic implications across human cancer DOI Open Access
Xin Qin, Jing Wang, Xing Wang

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 158, P. 114193 - 114193

Published: Dec. 29, 2022

DNA helicases are essential to genomic stability by regulating metabolisms and their loss-of-function mutations lead instability predisposition cancer. Paradoxically, overexpression of is observed in several cancers. Here we analyzed molecular alterations 12 important TCGA pan-cancers provide an overview aberrations. Significant expression heterogeneity was observed. We calculated helicase score (DHS) based on expression, categorized tumors into high, low intermediate subtypes. High DHS subtypes were robustly associated with stemness, proliferation, hyperactivated oncogenic signaling, longer telomeres, total mutation burden, copy number (CNAs) shorter survival. Importantly, high DHSs exhibited stronger alternative end-join (alt-EJ) factors, indicative sensitivity chemo- radio-therapies. also homologous recombination deficiency (HRD), BRCA1/2 PARP inhibitors. Moreover, drugs identified inhibit helicases, the Auror A kinase inhibitor Danusertib as strongest candidate that confirmed experimentally. The aberrant CNAs, methylation m6A regulators. Our findings thus reveal widespread dysregulation broad connection featured aberrations across human close association alt-EJ pathway HRD, identification a putative have translational significance. Taken together, these will contribute helicase-based cancer therapy.

Language: Английский

Citations

3
Unraveling the mechanisms of RECQL4-mediated cervical cancer progression through the PI3K/AKT pathway DOI Creative Commons
Wen Huo,

Yiheng Huang,

Baoqinq Tian

et al.

Translational Oncology, Journal Year: 2024, Volume and Issue: 50, P. 102146 - 102146

Published: Oct. 7, 2024

Language: Английский

Citations

0