Trends in Cell Biology
Volume 27, Issue 12, December 2017, Pages 917-930
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Review
Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis

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Chromothripsis is a catastrophic event in which one or a few chromosomes are shattered and stitched back together in random order, producing a derivative chromosome with complex rearrangements within a few cell cycles.

Chromosome mis-segregation during cell division frequently produces small nuclear structures called micronuclei, which are prone to irreversible nuclear envelope disruption during interphase and impaired nucleocytoplasmic compartmentalization.

Micronucleated chromosomes accumulate extensive DNA damage and are susceptible to shattering during the next mitosis, generating multiple, distinct DNA fragments.

Chromosome fragments are reassembled by DNA double-strand break repair to form a derivative chromosome.

Chromatin bridges trapped between daughter cells are attacked by a cytoplasmic nuclease (three-prime repair exonuclease 1; TREX1) during interphase to generate DNA breaks and focal chromothripsis.

Cancer genome sequencing has identified chromothripsis, a complex class of structural genomic rearrangements involving the apparent shattering of an individual chromosome into tens to hundreds of fragments. An initial error during mitosis, producing either chromosome mis-segregation into a micronucleus or chromatin bridge interconnecting two daughter cells, can trigger the catastrophic pulverization of the spatially isolated chromosome. The resultant chromosomal fragments are religated in random order by DNA double-strand break repair during the subsequent interphase. Chromothripsis scars the cancer genome with localized DNA rearrangements that frequently generate extensive copy number alterations, oncogenic gene fusion products, and/or tumor suppressor gene inactivation. Here we review emerging mechanisms underlying chromothripsis with a focus on the contribution of cell division errors caused by centromere dysfunction.

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

References (81)

  • M.J. Jones et al.

    Chromothripsis: chromosomes in crisis

    Dev. Cell

    (2012)
  • C. Cheng

    Whole-genome sequencing reveals diverse models of structural variations in esophageal squamous cell carcinoma

    Am. J. Hum. Genet.

    (2016)
  • J. Maciejowski

    Chromothripsis and kataegis induced by telomere crisis

    Cell

    (2015)
  • M. Terradas

    DNA lesions sequestered in micronuclei induce a local defective-damage response

    DNA Repair (Amst.)

    (2009)
  • E.M. Hatch

    Catastrophic nuclear envelope collapse in cancer cell micronuclei

    Cell

    (2013)
  • J. Irianto

    DNA damage follows repair factor depletion and portends genome variation in cancer cells after pore migration

    Curr. Biol.

    (2017)
  • H. Ghezraoui

    Chromosomal translocations in human cells are generated by canonical nonhomologous end-joining

    Mol. Cell

    (2014)
  • A. Royou

    BubR1- and Polo-coated DNA tethers facilitate poleward segregation of acentric chromatids

    Cell

    (2010)
  • D.H. Lee

    Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks

    Mol. Cell

    (2014)
  • D.W. Garsed

    The architecture and evolution of cancer neochromosomes

    Cancer Cell

    (2014)
  • B. van Steensel

    TRF2 protects human telomeres from end-to-end fusions

    Cell

    (1998)
  • J.A. Lee

    A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders

    Cell

    (2007)
  • W.P. Kloosterman

    Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms

    Cell Rep.

    (2012)
  • L. Yang

    Diverse mechanisms of somatic structural variations in human cancer genomes

    Cell

    (2013)
  • D.H. McDermott

    Chromothriptic cure of WHIM syndrome

    Cell

    (2015)
  • C. Tyler-Smith

    Transmission of a fully functional human neocentromere through three generations

    Am. J. Hum. Genet.

    (1999)
  • B.E. Black et al.

    Epigenetic centromere propagation and the nature of CENP-a nucleosomes

    Cell

    (2011)
  • R. Ceccaldi

    Repair pathway choices and consequences at the double-strand break

    Trends Cell. Biol.

    (2016)
  • D. Ottaviani

    The role of microhomology in genomic structural variation

    Trends Genet.

    (2014)
  • A. Sfeir et al.

    Microhomology-mediated end joining: a back-up survival mechanism or dedicated pathway?

    Trends Biochem. Sci.

    (2015)
  • P.C. Nowell et al.

    Minute chromosome in human chronic granulocytic leukemia

    Science

    (1960)
  • B.J. Druker

    Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia

    N. Engl. J. Med.

    (2001)
  • F. Notta

    A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns

    Nature

    (2016)
  • L.B. Alexandrov

    Signatures of mutational processes in human cancer

    Nature

    (2013)
  • J.J. Molenaar

    Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

    Nature

    (2012)
  • M. Parker

    C11orf95-RELA fusions drive oncogenic NF-kappaB signalling in ependymoma

    Nature

    (2014)
  • J. George

    Comprehensive genomic profiles of small cell lung cancer

    Nature

    (2015)
  • A. Scarpa

    Whole-genome landscape of pancreatic neuroendocrine tumours

    Nature

    (2017)
  • M. Fraser

    Genomic hallmarks of localized, non-indolent prostate cancer

    Nature

    (2017)
  • W.P. Kloosterman

    Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline

    Hum. Mol. Genet.

    (2011)
  • Cited by (0)

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