Mechanisms of genome stability maintenance during cell division
Mara De Marco Zompit, Manuel Stucki
Abstract
During mitosis, chromosomes undergo extensive structural changes resulting in the formation of compact cylindrical bodies and in the termination of the bulk of DNA-dependent metabolic activities. Therefore, DNA lesions that interfere with processes such as DNA replication and transcription in interphase are not expected to pose a major threat to genome stability in mitosis. There are, however, a few exceptions. DNA replication and repair intermediates that physically interconnect the sister chromatids jeopardize faithful chromosome segregation and need to be resolved before the onset of anaphase. In addition, dicentric chromosomes can form chromatin bridges and induce breakage-fusion-breakage cycles with dire consequences for genome stability. Finally, chromosome breaks that escape the G2/M DNA damage checkpoint or emerge early in mitosis may result in lagging acentric DNA fragments that mis-segregate and form micronuclei when cells exit from mitosis. Both chromatin bridges and micronuclei are potential sources of a mutational cascade that results in massive chromosomal instability and significantly contributes to genomic complexity. Here, we review recent progress in our understanding of the origins and consequences of chromosome bridges and micronuclei and the mechanisms by which cells suppress them.