Chromosome Segregation Errors as a Cause of DNA Damage and Structural Chromosome Aberrations

TLDR

Chromosomal aberrations such as aneuploidy and structural changes are common in human tumors, with aneuploidy arising from segregation errors and structural aberrations from misrepaired DNA breaks. The study aims to show that chromosome segregation errors can generate structural chromosome aberrations. Mis‑segregated chromosomes are damaged during cytokinesis, activating an ATM/Chk2/p53‑mediated double‑strand break response in daughter cells. The data reveal that double‑strand breaks from segregation errors cause unbalanced translocations, highlighting the contribution of whole‑chromosome instability to tumorigenesis.

Abstract

Various types of chromosomal aberrations, including numerical (aneuploidy) and structural (e.g., translocations, deletions), are commonly found in human tumors and are linked to tumorigenesis. Aneuploidy is a direct consequence of chromosome segregation errors in mitosis, whereas structural aberrations are caused by improperly repaired DNA breaks. Here, we demonstrate that chromosome segregation errors can also result in structural chromosome aberrations. Chromosomes that missegregate are frequently damaged during cytokinesis, triggering a DNA double-strand break response in the respective daughter cells involving ATM, Chk2, and p53. We show that these double-strand breaks can lead to unbalanced translocations in the daughter cells. Our data show that segregation errors can cause translocations and provide insights into the role of whole-chromosome instability in tumorigenesis.