Trends in Cell Biology
ReviewRebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis
Section snippets
Hidden in Plain Sight: Chromothripsis in the Cancer Genome
The karyotypes of cancer cells are often remarkably complex – littered not only with mutations but also small- and large-scale changes in both chromosome number and architecture. Copy number alterations in the form of whole-chromosome or segmental aneuploidy are present in most tumors, yet its role as a cause or consequence of cancer development remains under debate 1, 2. Structural aberrations and gross rearrangements alter the linear organization of chromosomes, and in some instances can
Chromothripsis Driving Tumorigenesis
How does chromothripsis contribute to cancer development? The simultaneous formation of a multiple alterations through chromothripsis can lead to the acquisition of one or more selective advantages (Figure 1A). Because chromothripsis can result in both the loss of DNA segments and the formation of de novo rearrangements, two obvious culprits are the disruption of tumor suppressor genes and the formation of oncogenic fusion products, respectively. Rearrangements formed between two normally
The Micronucleus Revisited
At the exit of mitosis, nuclear lamins and pore complexes redeposit around newly segregated chromosomal masses to encapsulate the genome within the nuclear envelope (NE), ultimately forming the cell nucleus. A chromosome that fails to correctly segregate to either of the two mitotic spindle poles, perhaps due to improper kinetochore–microtubule attachments, will produce a micro-NE assembled around the lagging chromosome. The resultant micronucleus spatially isolates one or sometimes few
Sources of Micronuclear DNA Damage
In mammalian cells, why might micronuclear chromosomes acquire DNA damage in the form of DSBs? As micronucleated cells progress through interphase (Figure 3), the micro-NE has a tendency to undergo disruption that causes abrupt loss of nuclear contents (as detected by loss of GFP fused to nuclear import sequences) [41]. Correspondingly, the sequestered chromatin becomes exposed to normally cytoplasmic-localized components that diffuse into the micronucleus [41]. Thus, disruption of the micro-NE
One Centromere Too Few: Chromothripsis Driven by Centromere Inactivation
Several experimental approaches have been used to investigate the properties of micronuclei and the eventual fate of the encapsulated chromosome [52]. One widely used method to generate micronuclei is through prolonged mitotic arrest using microtubule inhibitors, such as nocodazole, followed by release and subsequent mis-segregation of one or few random chromosomes. An alternative experimental approach was recently developed involving the inactivation of a specific centromere (Box 2) to induce
Bringing It All Back Home: Reassembly through DNA Repair
Most DNA fragments produced by chromosome shattering are acentric [26], which alone are incapable of attaching to the mitotic spindle. The resulting fragments are therefore, at best, passively distributed, with likely asymmetric partitioning into newly formed daughter cells and reintegration into the main nucleus if they are in close proximity to either of the poleward-segregating chromosome masses (Figure 4A). The ends of these fragments are presumably recognized as DNA DSBs in the subsequent
One Centromere Too Many: Chromothripsis Driven by Dicentric Chromosomes
In certain instances, a single chromosome can harbor two active centromeres that are capable of attaching to the mitotic spindle. These dicentric chromosomes can be formed through several mechanisms. A neocentromere can spontaneously form at a non-centromeric region on the chromosome arm; an event that naturally occurs at a rare frequency through poorly defined mechanisms (Box 2). Most often and perhaps by telomere shortening, a dicentric can be produced by an end-to-end fusion event between
Alternative Mechanisms and Forms of Chromothripsis
A fraction of chromothriptic breakpoint junctions contain microhomology [10], suggesting potential repair by alt-EJ (Box 3) or the involvement of other mechanisms for localized rearrangements that are independent of chromosome shattering events, such as chromoanasynthesis. Mechanisms that have been proposed to contribute to the complex structural rearrangements defined by chromoanasynthesis include errors in DNA replication, most notably aberrant DNA template switching at stalled forks (called
Concluding Remarks
The discovery of chromothripsis has advanced our understanding of the complexities associated with cancer genomes, as well as opened exciting new avenues for research. The development of novel cell biological tools combined with computational methods to examine the fate and sequence characteristics of mis-segregated chromosomes has recently contributed to defining the mechanisms underlying chromothripsis. Much remains to be determined (see Outstanding Questions); in particular, the exact causes
Disclaimer Statement
The authors declare no conflicts of interest.
Acknowledgments
We thank M. Hetzer, E. Hatch, and D. Pellman for sharing original data images. This work was supported by grants from the National Institutes of Health (R35 GM122476 to D.W.C. and K99 CA218871 to P.L.) and the Hope Funds for Cancer Research (HFCR-14-06-06 to P.L.). D.W.C. receives salary support from the Ludwig Institute for Cancer Research.
Glossary
- Acentric
- a chromosome, or fragment of a chromosome, that lacks an active centromere.
- Centromere
- a specialized region on each chromosome designated for assembly of the kinetochore and whose unique position is identified and maintained epigenetically.
- Chromoanagenesis
- a catch-all term that encompasses catastrophic mutational processes involving one or a few chromosomes, independent of the precise mechanisms; included here are chromothripsis and chromoanasynthesis, which arise through distinct
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