Researchers found that blocking a key DNA repair protein destabilizes rogue DNA circles that help drive aggressive cancers, exposing a potential weakness in tumors that rely on ecDNA. Some aggressive cancers carry extra copies of cancer-driving genes on circles of DNA that float outside the cell’s normal chromosomes. These rogue DNA circles can help tumors grow faster, resist treatment, and become harder to control, yet their unusual structure raises a puzzle: how do cancer cells keep such unstable genetic material from falling apart? Known as extrachromosomal DNA, or ecDNA, these circular fragments occur in roughly 1 in 6 human cancers. ecDNA can amplify cancer-causing genes, and its presence has been linked to faster tumor growth, treatment resistance, and poorer survival. Scientists, however, have not completely understood how cancer cells preserve these fragile circles long enough to gain those advantages. A hidden weakness in ecDNA Researchers at Memorial Sloan Kettering Cancer Center (MSK) and their collaborators have now identified a two-part system that protects ecDNA from damage. The work, published in Nature, also revealed a structural weakness that could potentially be exploited to selectively destabilize ecDNA in cancer cells. The team, led by the lab of Agnel Sfeir, PhD, at MSK’s...

Researchers found that blocking a key DNA repair protein destabilizes rogue DNA circles that help drive aggressive cancers, exposing a potential weakness in tumors that rely on ecDNA.

Researchers found that blocking a key DNA repair protein destabilizes rogue DNA circles that help drive aggressive cancers, exposing a potential weakness in tumors that rely on ecDNA. Some aggressive cancers carry extra copies of cancer-driving genes on circles of DNA that float outside the cell’s normal chromosomes. These rogue DNA circles can help tumors [...]

Stability of extrachromosomal DNA (ecDNA) relies on microhomology-mediated end joining at fragile TA-rich sites, with FANCM suppressing break formation, suggesting that Polθ disruption may destabilize ecDNA and sensitize ecDNA-driven tumours to therapeutic intervention.

Stability of extrachromosomal DNA (ecDNA) relies on microhomology-mediated end joining at fragile TA-rich sites, with FANCM suppressing break formation, suggesting that Polθ disruption may destabilize ecDNA and sensitize ecDNA-driven tumours to therapeutic intervention.

Stability of extrachromosomal DNA (ecDNA) relies on microhomology-mediated end joining at fragile TA-rich sites, with FANCM suppressing break formation, suggesting that Polθ disruption may destab...

COLO320DM, COLO320HSR and SNU-16 cells (ATCC CCL-220, CCL-220.1 and CRL-5974, respectively) were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 100 U ml−1 penicillin-streptomycin, 1% non-essential amino acids, and 2 mM l-glutamine. HEK293T cells (ATCC CRL-3216), PC3-DM, and PC3-HSR (gifts from the P. Mischel laboratory) were cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% bovine calf serum, 100 U ml−1 penicillin-streptomycin, 1% non-essential amino acids, and 2 mM l-glutamine. NCI-H716 cells (ATCC CCL-251) were cultured in RPMI-1640 with the same supplements. All cells were incubated at 37 °C in a humidified atmosphere containing 5% CO2. All cells were tested for Mycoplasma by PCR. HeLa cells were cultured as previously described7. In brief, cells were grown in DMEM supplemented with 10% FBS (Omega), 100 U ml−1 penicillin, 100 U ml−1 streptomycin, and 2 mM l-glutamine. For MTX experiments, dialysed FBS was used. Specific HeLa-derived clones were used at the following MTX concentrations: PD29424h (H, DM+, 60 nM MTX) and PD29426a (HSR+, 40 nM MTX). Adult neuronal stem cells (aNSCs) from Mycec/+; Trp53fl/fl (ecMyc) or control Myc+/+; Trp53fl/fl (control) mice were isolated and cultured in adherent condition on laminin-coated (Sigma-Aldrich, L2020) dishes in NeuroCult Stem Cell Basal...

Researchers at Memorial Sloan Kettering Cancer Center (MSK) and their colleagues have discovered that a type of rogue DNA found in aggressive cancers has a hidden structural weakness—and that blocking a single repair protein can cause it to fall apart, suggesting a new therapeutic opportunity.

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Plasmids in bacteria and extrachromosomal DNA in cancer both generate copy-number variation, alter gene expression and promote rapid adaptation. In this Perspective, Shaw and Henssen explore their sha...

Kuzminov, A. Bacterial nucleoid is a riddle wrapped in a mystery inside an enigma. J. Bacteriol. 206, e0021123 (2024). Castañeda-Barba, S., Top, E. M. & Stalder, T. Plasmids, a molecular cornerstone of antimicrobial resistance in the One Health era. Nat. Rev. Microbiol. 22, 18–32 (2024). Jaworski, J. J. et al. ecDNA replication is disorganized and vulnerable to replication stress. Nucleic Acids Res. 53, gkaf711 (2025). Kang, X. et al. Extrachromosomal DNA replication and maintenance couple with DNA damage pathway in tumors. Cell 188, 3405–3421.e27 (2025). Sankar, V. et al. Genetic elements promote retention of extrachromosomal DNA in cancer cells. Nature 649, 152–160 (2025). Kraft, K. et al. Enhancer activation from transposable elements in extrachromosomal DNA. Nat. Cell Biol. 27, 1914–1924 (2025). Pradella, D. et al. Engineered extrachromosomal oncogene amplifications promote tumorigenesis. Nature 637, 955–964 (2025). Yi, E., Chamorro González, R., Henssen, A. G. & Verhaak, R. G. W. Extrachromosomal DNA amplifications in cancer. Nat. Rev. Genet. 23, 760–771 (2022). Cox, D., Yuncken, C. & Spriggs, A. I. Minute chromatin bodies in malignant tumours of childhood. Lancet 1, 55–58 (1965). Lubs, H. A. Jr & Salmon, J. H. The chromosomal complement of human solid tumors. II. Karyotypes of glial tumors. J...

Extrachromosomal DNAs (ecDNAs) attach to chromosomes during mitosis for random segregation and promote cancer heterogeneity. However, the mechanism governing ecDNA–chromosome mitotic interactions remains poorly understood. Here we show that ecDNAs tether to histone H3 lysine 27 acetylation (H3K27ac)-marked chromatin during mitosis. Depleting H3K27ac disrupts this interaction. Diverse bromodomain proteins, as H3K27ac readers, stabilize ecDNA–chromosome binding in a context-dependent and complementary manner. Although disrupting the Mediator complex in asynchronous cells detaches ecDNAs from mitotic chromosomes, Mediator and active Pol II are absent from ecDNAs during mitosis, suggesting that ecDNAs are transcriptionally silent during mitosis. Instead, inactive Pol II mediates ecDNA attachment. Furthermore, CRISPR interference targeting transcriptional regulatory elements on ecDNA impairs ecDNA segregation. Mis-segregated ecDNAs were expelled into the cytosol, leading to diminished oncog

2026.09.07 がん研究会 プレスリリース 1. ポイントがん細胞の中には、染色体から独立した環状のDNA「染色体外DNA(ecDNA)」(注1)が存在し、MYCなどのがん遺伝...

Ovarian cancer is notoriously difficult to detect early, with most patients diagnosed only once the disease has spread throughout the abdomen. At this advanced stage, treatment options are limited and...

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