# Mitotic chromatin compaction tethers extrachromosomal DNA to chromosomes and prevents their mis-segregation into micronuclei

## TL;DR

Extrachromosomal DNA (ecDNA) is tethered to chromosomes during cell division through chromatin compaction, preventing its mis-segregation into micronuclei and contributing to cancer progression.

## Contribution

This study identifies chromatin compaction as a key mechanism for tethering ecDNA to chromosomes during mitosis.

## Key findings

- Decompacting mitotic chromatin leads to ecDNA mis-segregation into micronuclei.
- Overexpression of Ki67 also causes ecDNA mis-segregation into micronuclei.
- Chromatin compaction mechanisms are crucial for tethering ecDNA to chromosomes.

## Abstract

Extrachromosomal DNA (ecDNA) is linked to aggressive cancer growth, treatment resistance, and shorter survival across a wide variety of cancers. ecDNA promotes intratumoral genetic heterogeneity, enhanced oncogene expression, and accelerated tumor evolution, driving tumor pathogenesis. ecDNA lacks centromeres and segregates to daughter cell nuclei during mitosis by tethering to chromosomes. However, the mechanisms involved in this tethering are incompletely understood. Here, I present evidence that ecDNA tethering to chromosomes is coupled with chromatin compaction during mitotic chromosome formation, which acts to generally increase chromatin-chromatin interaction. Using a cancer cell line model, I show that decompacting mitotic chromatin under hypotonic conditions and by increasing histone acetylation untethers ecDNA from chromosomes, leading to their mis-segregation into micronuclei after mitosis. Additionally, overexpression of the mitotic chromosome surfactant Ki67 untethers ecDNA from chromosomes, leading to their mis-segregation into micronuclei. These findings show that the mechanisms involved in chromatin compaction are important for tethering ecDNA to chromosomes and preventing their mis-segregation into micronuclei. I propose a model in which interactions between ecDNA chromatin fibers and chromosomal chromatin contribute to ecDNA segregation into daughter cells during cell division.