Nuclear Architecture, Chromosome Aberrations, and Genetic Damage

Mammalian interphase nuclei are highly organized structures in which chromosome territories are nonrandomly distributed following a radial pattern. Gene richness and size markedly influence nuclear chromosome positioning. Active euchromatin and inactive heterochromatin exhibit different nuclear topology: the former is centrally located and the latter mostly placed at the periphery, within chromocenters, and around nucleoli. DNA is subjected to a wide repertoire of insults including radiation, chemical, and biological agents. The differential sensitivity of euchromatin and heterochromatin to clastogens has been a matter of debate, although most experimental evidence supports that euchromatin is more damage prone. Gene expression and DNA synthesis coupled to chromatin remodeling could act as key factors in the distribution of chromosome aberrations (CA) in euchromatic and heterochromatic regions of genome. In this chapter, the main features of nuclear architecture as well as an overview of current knowledge of genetic damage at the metaphase and interphase levels are presented. Also, the preferential involvement of transcriptionally active regions of the human genome regarding the induction of chromosome aberrations and deregulation of tumor genes is analyzed. Finally, the impact of DNA replication timing and connected chromatin remodeling processes in the generation and localization of CA and primary genetic damage is discussed.