Ionizing Radiation Induces Frequent Translocations with Delayed Replication and Condensation

Abstract

Certain chromosome rearrangements display a significant delay in replication timing that is associated with a delay in mitotic chromosome condensation. Chromosomes with delay in replication timing/delay in mitotic chromosome condensation participate in frequent secondary rearrangements, indicating that cells with delay in replication timing/delay in mitotic chromosome condensation display chromosomal instability. In this report, we show that exposing cell lines or primary blood lymphocytes to ionizing radiation results in chromosomes with the delay in replication timing/delay in mitotic chromosome condensation phenotype, and that the delay in replication timing/delay in mitotic chromosome condensation phenotype occurs predominantly on chromosome translocations. In addition, exposing mice to ionizing radiation also induces cells with delay in replication timing/delay in mitotic chromosome condensation chromosomes that persist for as long as 2 years. Cells containing delay in replication timing/delay in mitotic chromosome condensation chromosomes frequently display hyperdiploid karyotypes, indicating that delay in replication timing/delay in mitotic chromosome condensation is associated with aneuploidy. Finally, using a chromosome engineering strategy, we show that only a subset of chromosome translocations displays delay in replication timing/delay in mitotic chromosome condensation. Our results indicate that specific chromosome rearrangements result in the generation of the delay in replication timing/delay in mitotic chromosome condensation phenotype and that this phenotype occurs frequently in cells exposed to ionizing radiation both in vitro and in vivo.

Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability

“…Cells containing chromosomes with DRT/DMC induced by exposure to IR often contain hyperdiploid karyotypes (Breger et al, 2004). In this report, we show that introduction of a DRT/DMC chromosome into a karyotypically stable cell line results in centrosome amplification, abnormal mitotic spindles, endoreduplication and abnormal numbers of chromosomes.…”

“…DRT/DMC chromosomes are common in tumor cells and occur frequently in cells exposed to ionizing radiation (IR) (Smith et al, 2001;Breger et al, 2004). In this report, we found that DNA synthesis could be detected on DRT/DMC chromosomes during mitosis, and that DRT/DMC chromosomes contain phosphorylated Chk1.…”

“…Centrosome amplification, abnormal spindle assembly, endoreduplication and CIN DRT/DMC chromosomes often contained abnormal mitotic figures and hyperdiploid karyotypes (Smith et al, 2001;Breger et al, 2004). Therefore, we analysed centrosome copy number and mitotic spindles using antibodies against g-and b-tubulin, respectively.…”

Radiation-induced transgenerational alterations in genome stability and DNA damage

“…Indeed, the results of recent studies suggest that in human precancerous cells, the ataxia-telangiectasia Rad3-related/ataxia-telangiectasia mutated-regulated checkpoints are activated through deregulated DNA replication, which leads to multiple types of DNA alterations (Bartkova et al, 2005;Gorgoulis et al, 2005). It has also been shown that radiation-induced chromosome instability in vitro could be attributed to the long-term delay in chromosome replication (Breger et al, 2004). Given that our previous results suggest that the mechanism of ESTR mutation is most probably attributed to replication slippage (Yauk et al, 2002;Barber et al, 2004;Dubrova, 2005), delayed/stalled replication can therefore provide a plausible explanation for the transgenerational increases in mutation rate at these loci, as well as the multiplicity of DNA alterations detected in this work.…”

The Assessment of Cytogenetic Indices of Chernobyl Power Plant Disaster Liquidators

“…At present, the classical chromosome analysis of human blood lymphocytes is one of the available and widely used methods of the chromosome instability assessment of the radiation-exposed human population [6], [7]. The character of structural reconstruction and frequency depend on the type of ionizing radiation [8], [9].…”