Chromosomal tethering and mitotic transcription promote ecDNA nuclear inheritance Journal Article
| Authors: | Nichols, A.; Choi, Y.; Norman, R. X.; Chen, Y.; Striepen, J.; Salataj, E.; Toufektchan, E.; Koche, R.; Maciejowski, J. |
| Article Title: | Chromosomal tethering and mitotic transcription promote ecDNA nuclear inheritance |
| Abstract: | Extrachromosomal DNAs (ecDNAs) are circular DNAs that function in tumor progression and treatment resistance by amplifying oncogenes. ecDNAs lack centromeres and thus are not constrained to Mendelian segregation, enabling unequal and rapid accumulation within daughter cells. Despite intrinsic links to their oncogenic potential, the fidelity and mechanisms of ecDNA inheritance are poorly understood. Using human cancer cell lines, we show that ecDNAs are protected against cytosolic mis-segregation through mitotic clustering and tethering to mitotic chromosome ends. Accurate nuclear segregation of MYC-amplifying ecDNA depends on BRD4 transcriptional co-activation and mitotic transcription of the long non-coding RNA PVT1, which is frequently co-amplified with MYC. Disruption of ecDNA mitotic clustering through BRD4 inhibition, PVT1 depletion, or transcription inhibition causes ecDNA micronucleation and formation of homogeneously staining regions. We propose that nuclear inheritance of ecDNA is facilitated by an RNA-based mechanism that clusters ecDNA during mitosis and protects against cytosolic mis-segregation and chromosomal reintegration. © 2025 Elsevier Inc. |
| Keywords: | myc; pvt1; homogeneously staining region; micronuclei; ecdna; genome amplification |
| Journal Title: | Molecular Cell |
| Volume: | 85 |
| Issue: | 15 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Publication status: | Published |
| Date Published: | 2025-08-07 |
| Online Publication Date: | 2025-07-03 |
| Start Page: | P2839 |
| End Page: | P2853 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2025.06.013 |
| PROVIDER: | scopus |
| PMCID: | PMC12233203 |
| PUBMED: | 40614723 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is John Maciejowski -- Source: Scopus |
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