Too much to handle — how gaining chromosomes destabilizes the genome

Abstract

Most eukaryotic organisms are diploid, with 2 chromosome sets in their nuclei. Whole chromosomal aneuploidy, a deviation from multiples of the haploid chromosome number, arises from chromosome segregation errors and often has detrimental consequences for cells. In humans, numerical aneuploidy severely impairs embryonic development and the rare survivors develop disorders characterized by multiple pathologies. Moreover, as many as 75 % of malignant tumors display aneuploidy. Although the exact contribution of aneuploidy to tumorigenesis remains unclear, previous studies have suggested that aneuploidy may affect the maintenance of genome integrity. We found that human cells with extra chromosomes showed phenotypes suggestive of replication defects, a phenomenon which we went on to characterize as being due to the aneuploidy-driven downregulation of replication factors, in particular of the replicative helicase MCM2-7. Thus, missegregation of even a single chromosome can further promote genomic instability and thereby contribute to tumor development. In this review we will examine the possible causes of downregulation of replicative factors and discuss the consequences of genomic instability in aneuploid cells.