Role of Chromatin Structure and Activity in the Induction of Chromosomal Aberrations

Abstract

It is assumed that unrepaired or misrepaired DNA double-strand breaks lead to chromosomal aberrations. However, little information is available about the role of chromatin structure and remodelling in the formation of double-strand breaks and their processing into chromosome damage. Open chromatin conformation, recognized as euchromatin, possesses transcriptional activity, while tighter chromatin conformation, named heterochromatin, remains transcriptionally inactive. A higher order of differential chromatin structure can be observed at the chromosome level as banding patterns. In order to study the role of chromatin organization and activity in the induction of chromosomal aberrations, different approaches were employed: (1) analysis of the distribution of chromosome breakpoints induced by ionizing radiation (neutrons or ©-rays) in relation to the CHO G-banding pattern; (2) correlation of the CHO chromosome H4 acetylation pattern with radiation-induced breakpoint localization; (3) study of the influence of chromatin remodelling processes related to DNA replication and cell cycle progression analysing etoposide-induced and methyl methanesulfonate induced breakpoints distributed along Xp (euchromatic) and Xq (heterochromatic) CHO X chromosome arms; (4) localization of ©-ray-induced breakpoints to euchromatin and heterochromatin by exposing human fibroblast lines with different numbers of X chromosomes. Several factors, such as chromatin activity, chromatin remodelling processes associated with DNA synthesis or cell cycle progression as well as chromatin compartmentalization in euchromatin, heterochromatin and G-bands, have been found associated with the non-random distribution of chromosome damage.