Changes in chromatin organization of human cells in response to genotoxic stress

Abstract

Evidence is accumulating that infliction of DNA damage can lead to spatial repositioning of chromatin. Mitomycin C (MMC)-induced interchanges between homologous chromosomes have been taken as cytological evidence for somatic pairing of human chromosomes. Pairing of specific chromosomal regions might differ dependent on biological states or activities, i.e. cell type, cell cycle phase, differentiation stage and diseases. However, the biological relevance of pairing is unclear. The aim of this thesis was to dissect the mechanisms that underlie the interaction between homologous chromosomes observed in metaphase and the interphase of the cell cycle. To reach this goal, we assessed the effect of genotoxic agents such as X-rays, UV radiation and MMC on the positioning of homologous chromosomal regions within the nucleus of human cells. Moreover, we examined the relationship between interphase pairing and processing of DNA damage that leads to exchange formation. We found that: (i) pairing of heterochromatic regions is a general response to genotoxic stress, (ii) pairing is correlated with exchanges between homologous chromosomes after exposure to the anticancer drug mitomycin C (MMC), (iii) pairing is genetically controlled by genes involved in the DNA damage response and (iv) processing of MMC-induced DNA damage is initiated in non-dividing cells.