Abstract
The higher-order organization of chromatin is well-established, with chromosomes occupying distinct positions within the interphase nucleus. Chromatin is susceptible to, and constantly assaulted by both endogenous and exogenous threats. However, the effects of DNA damage on the spatial topology of chromosomes are hitherto, poorly understood. This study investigates the organization of all 24 human chromosomes in lymphocytes from six individuals prior to- and following in-vitro exposure to genotoxic agents: hydrogen peroxide and ultraviolet B. This study is the first to report reproducible distinct hierarchical radial organization of chromosomes with little inter-individual differences between subjects. Perturbed nuclear organization was observed following genotoxic exposure for both agents; however a greater effect was observed for hydrogen peroxide including: 1) More peripheral radial organization; 2) Alterations in the global distribution of chromosomes; and 3) More events of chromosome repositioning (18 events involving 10 chromosomes vs. 11 events involving 9 chromosomes for hydrogen peroxide and ultraviolet B respectively). Evidence is provided of chromosome repositioning and altered nuclear organization following in-vitro exposure to genotoxic agents, with notable differences observed between the two investigated agents. Repositioning of chromosomes following genotoxicity involved recurrent chromosomes and is most likely part of the genomes inherent response to DNA damage. The variances in nuclear organization observed between the two agents likely reflects differences in mobility and/or decondensation of chromatin as a result of differences in the type of DNA damage induced, chromatin regions targeted, and DNA repair mechanisms.
Highlights
The nucleus is a highly complex and compartmentalized organelle that accommodates a wide spectrum of actions including: genome replication, transcription, splicing and DNA repair
This study has focused on genotoxic agents namely, hydrogen peroxide (H2O2) and ultraviolet (UV) radiation that are capable of inducing endogenous and exogenous DNA damage
Compared to the unexposed lymphocyte cultures there was an average of a 62% and 40.5% reduction in cellular proliferation in H2O2 and UVB treated cells respectively
Summary
The nucleus is a highly complex and compartmentalized organelle that accommodates a wide spectrum of actions including: genome replication, transcription, splicing and DNA repair. CTs appear to be highly partitioned with minimal interactions which seems to confer a fractal globule model for the genome at least on the megabase scale as shown by 3C studies [7]. This minimal interaction occurs exclusively in the periphery of CTs, is observed in higher eukaryotes and contrasts the situation in budding yeast, where CTs are less geographically defined and are characterized by a higher degree of intermingling [8]. Two models have emerged to describe the radial organization of CTs within the interphase nucleus, namely gene density and chromosome size
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