ファンコニ貧血

Ewing sarcoma (EwS) is a group of bone and soft-tissue cancers in children and young adults. Because EwS cells have pronounced sensitivity to radiation and chemotherapy-induced DNA damage, the oncoprotein EWS-FLI1 is likely to be involved in DNA repair. Here, we demonstrate that EWS-FLI1 causes a defect in microhomology-mediated end joining (MMEJ) repair. EWSR1 is a splicing factor that promotes the faithful splicing of the POLQ pre-mRNA, required for the expression of Polθ, a critical protein in the MMEJ pathway. Expression of EWS-FLI1 or depletion of EWSR1 causes increased POLQ exon 25 skipping, decreased Polθ expression, impaired MMEJ, and enhanced cellular sensitivity to inhibitors of the Fanconi anemia (FA), homologous recombination (HR), or non-homologous end joining (NHEJ) pathways, through the mechanism of synthetic lethality. Correction of POLQ exon 25 skipping restored Polθ expression and MMEJ activity in EwS. Inhibitors of the FA, HR, or NHEJ pathways may therefore provide a targeted therapy for EwS patients.

OBJECTIVES: The significance of long non-coding RNAs (lncRNAs) in glioblastoma multiforme (GBM) has been acknowledged, but their specific role in the pathogenesis of GBM has not been thoroughly investigatedr. This study aimed to investigate the involvement of lncRNAs in the pathogenesis of GBM. METHODS: We collected GBM tissues from four patients and corresponding para-carcinoma controls samples, and used HiSeq sequencing to generate lncRNA expression profiles in GBM. To identify lncRNAs associated with GBM, we employed Mendelian randomization (MR), leveraging the comprehensive extensive expression data obtained from HiSeq sequencing to infer causal relationships. Expression quantitative trait loci (eQTLs) for brain tissues were accessed from the Genotype-Tissue Expression (GTEx) Portal. Subsequently, we conducted an integrative analysis combining brain cancer genome-wide association study (GWAS) summary data (finn-b-C3_GBM) with eQTL data using MR. Differentially expressed lncRNAs were intersected with MR results to identify lncRNA candidates. Subsequently, the ENCORI database was used to identify genes regulated by the candidate lncRNAs, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. RESULT: A protein-protein interaction (PPI) network was constructed to identify hub genes associated with GBM, and these findings were validated using the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) tool. A total of 106 lncRNAs exhibited significant alterations in expression levels (|log2(fold change)| > 1 and P < 0.05) in GBM tissues. Through Mendelian randomization (MR) analysis, TMEM161B-AS1 emerged as a promising candidate lncRNA. Genes regulated by TMEM161B-AS1 were significantly enriched in biological processes such as DNA replication and repair, cellular response to DNA damage stimuli, and pathways including the peroxisome proliferator-activated receptor signaling pathway, nucleotide excision repair, and the Fanconi anemia pathway. The differential expression of hub genes CUL4A, RPA1, and BRIP1 was validated using the GEPIA2 database. CONCLUSIONS: These findings suggest pathways for the development of more precise and sensitive biomarkers for the diagnosis and management of GBM, which may ultimately enhance patient outcomes.

Homologous recombination deficiency (HRD) is an actionable vulnerability found in a substantial fraction of human cancers, yet current HRD-directed therapies are limited by toxicity, incomplete responses, and acquired resistance. Many DNA-damaging agents were developed before DNA repair biomarkers were available, suggesting that abandoned agents may harbor previously unrecognized genotype-selective activity. Here, through a focused screen of DNA-damaging agents in isogenic homologous recombination-proficient and -deficient models, we identify CB1954, a decades-old nitrobenzamide aziridine prodrug, as highly selective for BRCA2-deficient tumor cells. CB1954 forms DNA interstrand crosslinks independent of HR status, but selectively induces DNA-damage signaling, apoptosis, and loss of clonogenic survival in HR-deficient cells. Targeted DDR CRISPR screening and isogenic validation define a distinct repair dependency for the Fanconi anemia and homologous recombination pathways, with limited dependence on mismatch repair or nucleotide excision repair. Genetic and pharmacologic perturbation of NQO2, the bioactivating enzyme for CB1954, reveals a bifurcated mechanism in which NQO2-dependent activation selectively contributes to HRD cytotoxicity, while aziridine-dependent lesions likely account for residual activity in HR-proficient cells. CB1954 exhibits favorable preclinical pharmacokinetic properties and genotype-dependent antitumor activity in BRCA2-deficient xenografts. These findings reposition CB1954 as a historically overlooked HRD-selective agent and demonstrate that biomarker-guided profiling of DNA-damaging agents can uncover new opportunities for precision oncology.

Guanine-rich nucleic acid sequences can fold into G-quadruplex (G4) structures that regulate DNA replication, transcription, and translation. Fanconi anemia group J helicase (FANCJ) resolves G4 structures at stalled replication forks. Despite its central role in genome maintenance, the molecular basis of G4 recognition and unwinding by FANCJ has remained unclear. Here, we report cryo-EM structures of human FANCJ bound to a G4-containing DNA substrate and ATPγS. The structures reveal direct engagement of the G4 by the Fe-S domain. Structure-guided mutagenesis demonstrates that this interface is essential for G4 binding and unwinding. The structures further capture open and closed conformational states linked to ATP hydrolysis, providing a mechanism for directional translocation along 5' ssDNA and progressive G4 unwinding. Together, these findings establish the structural basis of G4 recognition by FANCJ and provide mechanistic insights into how disease-associated mutations linked to Fanconi anemia and breast cancer impair helicase function.

Fanconi anemia complement group I (FANCI), a core component of the Fanconi anemia pathway, has emerged as a potential oncogenic factor across multiple cancer types. Located on chromosome 15q26.1, FANCI encodes a protein named FANCI that forms a stable heterodimer with FANCD2, playing a central role in the DNA damage response and repair. Beyond its involvement in DNA repair, FANCI participates in ribosome biogenesis, meiosis, and mRNA export, underscoring its essential role in maintaining genomic stability. Although FANCI deficiency has traditionally been associated with Fanconi anemia, recent studies have demonstrated that FANCI is overexpressed in various malignancies, where it promotes tumor progression and correlates with poor prognosis. The expression and activity of FANCI are tightly regulated at multiple levels, including transcriptional and post-transcriptional regulation by transcription factors and non-coding RNAs, as well as post-translational modifications such as phosphorylation mediated by PP2A and ATR, monoubiquitination catalyzed by the FANCL-UBE2T complex, and deubiquitination by USP1-UAF1. This review summarizes the functional mechanisms of FANCI across diverse physiological and pathological processes, highlighting its role as a crucial molecular bridge linking genomic stability maintenance to cancer development, and emphasizing its potential as a promising therapeutic target in cancer.