Extrachromosomal DNA are circular, acentric elements that carry amplified oncogenes in many cancers. Lacking centromeres, they are not partitioned evenly at mitosis, which allows copy number to climb far beyond what chromosomal amplification achieves and generates the heterogeneity on which selection acts.
ecDNA (magenta) hitchhiking on mitotic chromosomes (cyan). From Nichols et al., Molecular Cell, 2025.
Uneven inheritance, however, is not the same as unreliable inheritance. Acentric elements ought to be lost from the nucleus at an appreciable rate, and they are not. Across a panel of cancer cell lines we found that ecDNA reach daughter nuclei with high fidelity, and live-cell imaging showed why. The elements ride on mitotic chromosomes, tracking with the chromosome ends as the cell divides.
The connection depends on transcription that persists through mitosis, at a point when most of the genome has fallen silent. Blocking mitotic transcription releases ecDNA from the chromosomes and drives them into the cytoplasm, where they form micronuclei or reintegrate into the genome as long tandem arrays.
Several questions follow. We do not know what physically bridges the circle and the chromosome, whether that link is made by RNA directly or by proteins gathered on nascent transcripts. We do not know which proteins populate the environment immediately around ecDNA, or which of them keep the elements attached and intact. We do not know how released elements reintegrate, which is a second and quite different route to oncogene amplification. And we are asking whether the circular form itself is required, or merely incidental.
Read more at maciejowskilab.org.
