DNA topoisomerase II inhibition potentiates osimertinib’s therapeutic efficacy in EGFR-mutant non–small cell lung cancer models DOI Creative Commons
Zhen Chen, Karin A. Vallega, Dongsheng Wang

et al.

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(10)

Published: March 7, 2024

Development of effective strategies to manage the inevitable acquired resistance osimertinib, an approved 3rd generation EGFR inhibitor for treatment mutant (EGFRm) non-small cell lung cancer (NSCLC), is urgently needed. This study reported that DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide (VP-16) synergistically decreased survival with enhanced induction damage apoptosis in osimertinib-resistant cells, suppressed growth tumors, delayed emergence osimertinib resistance. Mechanistically, Topo IIα levels EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting damage; these effects were lost lines possessing elevated IIα. elevation was also detected majority tissues relapsed from EGFR-TKI treatment. Enforced expression ectopic TOP2A gene sensitive conferred whereas knockdown restored their response undergo osimertinib-induced apoptosis. Together, results reveal essential role inhibition mediating therapeutic efficacy against NSCLC, providing scientific rationale targeting osimertinib.

Language: Английский

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity DOI Creative Commons
Yuanjiu Lei,

Jordyn J. VanPortfliet,

Yifan Chen

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(14), P. 3013 - 3032.e22

Published: June 22, 2023

Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, exact immunostimulatory features mtDNA and kinetics detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability promotes Z-form accumulation. Z-DNA binding protein 1 (ZBP1) stabilizes nucleates complex containing cGAS, RIPK1, RIPK3 to sustain STAT1 phosphorylation type I interferon (IFN-I) signaling. Elevated mtDNA, ZBP1 expression, IFN-I signaling are observed in cardiomyocytes after exposure Doxorubicin, first-line chemotherapeutic agent induces frequent cardiotoxicity cancer patients. Strikingly, mice lacking or protected from Doxorubicin-induced cardiotoxicity. Our findings reveal as cooperative partner for cGAS sustains responses highlight potential target heart failure other disorders where stress contributes interferon-related pathology.

Language: Английский

Citations

124
PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them DOI Open Access
Dongha Kim, Hye Jin Nam

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(15), P. 8412 - 8412

Published: July 29, 2022

PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. have shown promising outcomes since their clinical applications and recently been as maintenance treatment for cancer patients with BRCA mutations. also exhibit positive results even in without homologous recombination (HR) deficiency. Therapeutic effects successfully achieved; however, development of resistance was unavoidable. Approximately 40–70% likely to develop resistance. Here, we describe mechanisms action inhibitors, causes resistance, various efforts overcome Particularly, determined survival probability according expression patterns genes associated HR restoration, which critical inhibitor Furthermore, discuss innovative attempts degrade proteins by chemically modifying inhibitors. These would enhance efficacy or expand scope usage.

Language: Английский

Citations

71
Regulation of biological processes by intrinsically chiral engineered materials DOI
Baojin Ma, Alberto Bianco

Nature Reviews Materials, Journal Year: 2023, Volume and Issue: 8(6), P. 403 - 413

Published: May 17, 2023

Language: Английский

Citations

51
Structure and repair of replication-coupled DNA breaks DOI
Raphael Pavani,

Veenu Tripathi,

Kyle B. Vrtis

et al.

Science, Journal Year: 2024, Volume and Issue: 385(6710)

Published: June 20, 2024

Using CRISPR-Cas9 nicking enzymes, we examined the interaction between replication machinery and single-strand breaks, one of most common forms endogenous DNA damage. We show that fork collapse at leading-strand nicks generates resected single-ended double-strand breaks (seDSBs) are repaired by homologous recombination (HR). If these seDSBs not promptly repaired, arrival adjacent forks creates double-ended DSBs (deDSBs), which could drive genomic scarring in HR-deficient cancers. deDSBs can also be generated directly when bypasses lagging-strand nicks. Unlike produced independently replication, end resection nick-induced is BRCA1-independent. Nevertheless, BRCA1 antagonizes 53BP1 suppression RAD51 filament formation. These results highlight distinctive mechanisms maintain stability.

Language: Английский

Citations

28
Identification of a lncRNA/circRNA-miRNA-mRNA network in Nasopharyngeal Carcinoma by deep sequencing and bioinformatics analysis DOI Creative Commons
Shilei Liu, Xiaoxiao Li,

Qingming Xie

et al.

Journal of Cancer, Journal Year: 2024, Volume and Issue: 15(7), P. 1916 - 1928

Published: Jan. 1, 2024

Background: Accumulating evidence indicates that non-coding RNAs (ncRNA), including long (lncRNAs) and circular (circRNAs), can function as competitive endogenous (ceRNAs) by binding to microRNAs (miRNAs) regulating host gene expression at the transcriptional or post-transcriptional level.Dysregulation in ceRNA network regulation has been implicated occurrence development of cancer.However, lncRNA/circRNA-miRNA-mRNA regulatory is still lacking nasopharyngeal carcinoma (NPC).Methods: Differentially expressed genes (DEGs) were obtained from our previous sequencing data Gene Expression Omnibus (GEO).Gene Ontology (GO) Kyoto Encyclopedia Genes Genomes pathway (KEGG) used explore biological functions these common DEGs.Through a series bioinformatic analyses, was established.In additional, external GSE102349 test prognostic value hub mRNAs through Kaplan-Meier method.Results: We successfully constructed NPC, consisting 16 lncRNAs, 6 miRNAs, 3 circRNAs 10 found three (TOP2A, ZWINT, TTK) significantly associated with overall survival time (OS) patients. Conclusion:The revealed this study may help comprehensively elucidate mechanisms driving provide novel candidate biomarkers for evaluating prognosis NPC.

Language: Английский

Citations

18
ATM and IRAK1 orchestrate two distinct mechanisms of NF-κB activation in response to DNA damage DOI
Elodie Bournique, Ambrocio Sanchez, Sunwoo Oh

et al.

Nature Structural & Molecular Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Language: Английский

Citations

2
Structural insights into human topoisomerase 3β DNA and RNA catalysis and nucleic acid gate dynamics DOI Creative Commons
Xi Yang, Xuemin Chen, Wei Yang

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 19, 2025

Abstract Type IA topoisomerases (TopoIAs) are present in all living organisms. They resolve DNA/RNA catenanes, knots and supercoils by breaking rejoining single-stranded segments allowing the passage of another nucleic acid segment through break. Topoisomerase III-β (TOP3B), only RNA topoisomerase metazoans, promotes R-loop disassembly translation mRNAs. Defects TOP3B lead to severe neurological diseases. We a series cryo-EM structures human with its cofactor TDRD3 during cleavage DNA or RNA, thus elucidating roles divalent metal ions key enzyme residues each step catalytic cycle. also obtained structure an open-gate configuration that addresses long-standing question strand-passage mechanism. Our studies reveal how catalyzes both relaxation, while TOP3A acts on DNA.

Language: Английский

Citations

2
Resolution of R-loops by topoisomerase III-β (TOP3B) in coordination with the DEAD-box helicase DDX5 DOI Creative Commons

Sourav Saha,

Xi Yang, Shar-yin N. Huang

et al.

Cell Reports, Journal Year: 2022, Volume and Issue: 40(2), P. 111067 - 111067

Published: July 1, 2022

The present study demonstrates how TOP3B is involved in resolving R-loops. We observed elevated R-loops knockout cells (TOP3BKO), which are suppressed by transfection. R-loop-inducing agents, the topoisomerase I inhibitor camptothecin, and splicing pladienolide-B also induce higher TOP3BKO cells. Camptothecin- pladienolide-B-induced concurrent with induction of cleavage complexes (TOP3Bccs). RNA/DNA hybrid IP-western blotting show that physically associated Biochemical assays using recombinant oligonucleotides mimicking cleaves single-stranded DNA displaced R-loop RNA-DNA duplex. IP-mass spectrometry experiments reveal interacts helicase DDX5 independently TDRD3. Finally, we demonstrate epistatic a pathway parallel senataxin. propose decatenation model for resolution TOP3B-DDX5 protecting from R-loop-induced damage.

Language: Английский

Citations

45
DNA damage and transcription stress DOI Creative Commons
Larissa Milano, Amit Gautam, Keith W. Caldecott

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 84(1), P. 70 - 79

Published: Dec. 15, 2023

Genome damage and transcription are intimately linked. Tens to hundreds of thousands DNA lesions arise in each cell day, many which can directly or indirectly impede transcription. Conversely, the process gene expression is itself a source endogenous as result susceptibility single-stranded damage, conflicts with replication machinery, engagement by cells topoisomerases base excision repair enzymes regulate initiation progression Although such processes tightly regulated normally accurate, on occasion, they become abortive leave behind breaks that drive genome rearrangements, instability, death.

Language: Английский

Citations

35
Two distinct long-range synaptic complexes promote different aspects of end processing prior to repair of DNA breaks by non-homologous end joining DOI Creative Commons
Christopher J. Buehl, Noah J. Goff, Steven W. Hardwick

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(5), P. 698 - 714.e4

Published: Feb. 1, 2023

Language: Английский

Citations

30