Higher-Order Chromatin Structure and Nontargeted Effects

Abstract

Ionizing radiation causes deleterious effects in cells that have directly absorbed its energy as well as in those which are not exposed to radiation directly. The latter are often referred to as radiation-induced nontargeted effects. Radiationinduced genomic instability is one of those effects, and it is manifested as the expression of various delayed effects, such as delayed cell death, delayed chromosomal instability, and delayed mutagenesis. Because this instability accumulates genetic changes in the genome, it has been hypothesized to be a driving force to accelerate multistep carcinogenesis. Exposure to ionizing radiation causes doublestrand breaks in DNA, which result in deletion of the genome through illegitimate rejoining of the broken ends. Recently, we found that large deletions could be transmitted in the progeny of cells surviving ionizing radiation. As large deletions disrupt higher-order chromatin structure and chromatin codes, they possibly comprise potentially unstable chromatin regions, whose disintegration causes delayed manifestation of radiation-induced genomic instability. Our present study defi nes the molecular nature of DNA damage memory, which is associated with nontargeted effects.