Abstract C72: A mechanistic link between whole-chromosome aneuploidy and DNA damage

Abstract

Abstract Cancer is associated with aneuploidy— both structural defects in chromosomes and abnormal numbers of intact chromosomes. The contribution of chromosome breaks to tumorigenesis is well accepted because of the possibility of generating cancer-causing mutations. However, the role of alterations of intact chromosome numbers remains a subject of debate, principally because mechanisms by which whole chromosome aneuploidy would affect cancer pathogenesis are poorly understood. We now have evidence to support one mechanism by which whole chromosome aneuploidy can lead to DNA breaks, via mis-segregation of chromosomes into micronuclei, structures commonly observed in cancer cells. Micronuclei containing intact chromosomes can form after mitotic errors, when the nuclear envelope reforms around a lagging chromosome. We have developed procedures to monitor the fate of micronuclei. Strikingly, whole chromosome-containing micronuclei develop evidence of DNA breaks during the first S phase after they are formed. Blocking DNA replication blocks the formation of these breaks. Defective DNA replication may be due to defective nucleocytoplasmic transport because micronuclei display a marked defect in assembling nuclear pore complexes. These findings suggest one mechanism by which mitotic errors result in DNA damage and thus potentially promote tumorigenesis. Citation Information: Cancer Res 2009;69(23 Suppl):C72.