DNA breaks and chromosome pulverization from errors in mitosis

By K. Crasta, Neil J. Ganem, R. Dagher, A. Lantermann, E. Ivanova, Yunfeng Pan, L. Nezi, A. Protopopov, Dipanjan Chowdhury, D. Pellman. Nature, 2012

1,211 citations recorded by the source corpus.

The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for ‘chromothripsis’ in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement.

Subfields: Cell Biology, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/77f987d673a475dac137fa9a1cf7dec352bd8c4b

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In Molecular Biology

1. J. Haber
2. Thomas J. Deerinck
3. A. Fischer
4. M. Hetzer
5. Emily M. Hatch
6. Anuja S. Mehta

Citations in the corpus

• Catastrophic nuclear envelope collapse in cancer cell micronuclei (2013, background): “…suggest 0.5 to 2.5 MN occur per 1,000 human buccal cells) (Holland et al., 2008), we did observe MN disruption occurring in nontransformed cell lines, consistent with previous reports of g-H2AX-positive MN in these types of cells (Terradas et al., 2009; Xu et al., 2011; Crasta et al., 2012).”
• ATR prohibits replication catastrophe by preventing global exhaustion of RPA. (2013, neutral): “In exceptional cases, RC might be confined to micronuclei, which result from chromosome misalignment and tend to undergo uncoordinated DNA replication (Crasta et al., 2012).”
• Sources of DNA double-strand breaks and models of recombinational DNA repair. (2014, background): “It has recently been shown that, because of inefficient nuclear import, micronuclei fail to attain all of the required replication and repair components and, hence, show higher replication stress and DNA fragmentation (Crasta et al. 2012).”
• cGAS surveillance of micronuclei links genome instability to innate immunity (2017, positive): “Micronuclear DNA is particularly susceptible to DNA damage, leading to chromothripsis7,17.”
• Patterns of somatic structural variation in human cancer genomes (2020, neutral): “Chromothripsis 3 , in which chromosome shattering and rearrangement occur in a single catastrophic event 9,21 , leads to a pattern of oscillating copy number changes and localised clustering of tens to hundreds of breakpoints 22 .”
• Lessons from the cancer genome. (2013, neutral): “Genomic shattering appears to develop as a result of erroneous chromosome segregation during mitosis and the subsequent entrapment of individual chromosomes within ‘‘micronuclei’’ (Crasta et al., 2012).”