2026/06/24 by Yipeng Xie, Jun Yi Stanley Lim, Wenyue Liu +5 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Cancer Genomics and Diagnostics #Genomics and Chromatin Dynamics #Microtubule and mitosis dynamics
paper · doi:10.1038/s41556-026-01982-0
openalex publication_date 2026/06/24 · openalex created_date 2026/06/25 · openalex updated_date 2026/07/27
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 oncogene expression and a reversal of therapy resistance. Our research provides universal cis and trans regulatory mechanisms of ecDNA segregation, offering deeper insight into ecDNA-driven oncogenesis.