Abstract
Werner syndrome (WS) is an autosomal recessive disorder whose phenotype mimics premature aging. This syndrome is caused by mutations in WRN, a member of the RecQ DNA helicase family, of which biological function remains unclear. In the present study, we investigated the relationship between the dysfunction of WRN protein and chromosomal instability. Primary fibroblast cells (WS3RGB) derived from a WS patient showed chromosomal instability during cell culture with complex-type translocations including at least five chromosomes. In addition to this karyotype instability, the WS cells indicated high level (4.9%) of dicentric formation spontaneously. These findings imply that genomic instability accompanied by telomeric dysfunction is evident in the WS cells. Therefore, we asked telomeric stability of the WS cells by telomere-FISH technique. The result revealed that extra telomere signals (ETS) emerged more frequently (3%) than that in the control cells (0.8%). Interestingly, the frequency of ETS was elevated after exposure to 4NQO, a DNA damaging agent, suggesting that ETS was responsible for structural abnormality in telomeres by some DNA damage and that the complex-type translocations might be formed mediated by telomeric dysfunction. However, we did not have evidence to support telomere fusion in forming the translocations by subtelomere-FISH analysis. The present study demonstrates that telomeres in WS cells are constitutively unstable possibly due to WRN dysfunction, suggesting a crucial role of WRN protein in telomere maintenance.
