A matter of wrapper: Defects in the nuclear envelope of lagging and bridging chromatin threatens genome integrity

Abstract

The nuclear envelope surrounds the eukaryotic genome and, through the nuclear pore complexes, regulates transport in and out of the nucleus. Correct nucleo-cytoplasm compartmentations are essential for nuclear functions such as DNA replication or repair. During metazoan mitosis, the nuclear envelope disintegrates to allow the segregation of the two copies of DNA between daughter cells. At the end of mitosis, it reforms on each group of chromosomes in the daughter cells. However, nuclear envelope reformation is delayed on lagging chromosomes and DNA bridges. Defects in the coordination between nuclear envelope reformation and chromosome segregation impair the nuclear functions. Mechanical stress to which micronuclei and DNA bridges are subjected to combined with their particular architecture and the altered nuclear functions result in DNA damage. While micronuclei and DNA bridges were considered for more than 100 years as mere indicators of chromosomal instability, rapid technological advances are helping to better understand the biological consequences of these aberrant nuclear morphologies. Recent studies provide interesting evidence that micronuclei and chromatin bridges act as a key platforms for a catastrophic mutational process observed in cancers called chromothripsis and a trigger for the innate immune response. Therefore, they could affect cellular functions by both genetic and non-genetic means.

Keywords: Chromothripsis; DNA bridge; DNA damage; Micronucleus; Nuclear envelope.