Chromosomes trapped in micronuclei are liable to segregation errors

Abstract

DNA in micronuclei is likely to get damaged. When shattered DNA from micronuclei gets reincorporated into the primary nucleus, aberrant rearrangements can take place, a phenomenon referred to as chromothripsis. Here, we investigated how chromatids from micronuclei act in subsequent divisions and how this affects their fate. We observed that the majority of chromatids derived from micronuclei fail to establish a proper kinetochore in mitosis, which is associated with problems in chromosome alignment, segregation and spindle assembly checkpoint activation. Remarkably, we found that, upon their formation, micronuclei already display decreased levels of important kinetochore assembly factors. Importantly, these defects favour the exclusion of the micronucleus over the reintegration into the primary nucleus over several divisions. Interestingly, the defects observed in micronuclei are likely overcome once micronuclei are reincorporated into the primary nuclei, as they further propagate normally. We conclude that the formation of a separate small nuclear entity represents a mechanism for the cell to delay the stable propagation of excess chromosome(s) and/or damaged DNA, by inducing kinetochore defects.

Mechanisms Generating Cancer Genome Complexity From A Single Cell Division Error

“…Defective loading of CENP-A, presumably due to nuclear import defects, could contribute to centromere defects in chromosome bridges, as was recently reported for micronuclei (53). However, failure to load new CENP-A would only cause a 2-fold dilution each cell cycle, which on its own (54) would be unlikely to explain the timing and extent of chromosome mis-segregation we observed.…”

Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint

“…A major reason for that is that aneuploidy is notoriously difficult to study: it affects multiple genes at once, it plays distinct roles in different contexts, and it is hard to engineer experimentally. Moreover, a high degree of aneuploidy is closely associated with other genomic alterations, such as whole-genome duplication (WGD) and p53 inactivation 3,23,24 ; and with cell division defects, such as CIN and micronuclei formation [25][26][27] . Large-scale studies are therefore required in order to control for potentially-confounding factors, and isogenic in vitro systems are then required to validate differential dependencies and dissect them mechanistically.…”

“…As noted above, the degree of tumor aneuploidy is known to be associated with other genomic and cellular features, and in particular with tissue type, proliferation rate, CIN, WGD, and p53 function 3,5,6,[23][24][25][26][27] . Indeed, we found all of these features to be strongly associated with AS in cancer cell lines as well (Extended Data Fig.…”

Inflammatory signaling in genomically instable cancers

“…Therefore, DNA damage accumulates in micronuclei during Sand G2-phase of the cell cycle and leaves genomic regions under-replicated. Furthermore, chromatids in micronuclei that contain centromeric regions are defective in building a functional kinetochore and do not properly recruit spindle assembly checkpoint proteins [41]. Also, re-integration of damaged chromatin from micronuclei into the main nucleus, which occurs with almost 40% of the micronuclei, triggers replication problems, genomic instability and extensive genomic rearrangements involving chromotripsis [37,42,43].…”