Rebuilding Chromosomes After Catastrophe: Emerging
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Review Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis 1, 1, Peter Ly * and Don W. Cleveland * Cancer genome sequencing has identified chromothripsis, a complex class of Trends structural genomic rearrangements involving the apparent shattering of an Chromothripsis is a catastrophic event individual chromosome into tens to hundreds of fragments. An initial error in which one or a few chromosomes are shattered and stitched back during mitosis, producing either chromosome mis-segregation into a micronu- together in random order, producing cleus or chromatin bridge interconnecting two daughter cells, can trigger the a derivative chromosome with com- catastrophic pulverization of the spatially isolated chromosome. The resultant plex rearrangements within a few cell cycles. chromosomal fragments are religated in random order by DNA double-strand break repair during the subsequent interphase. Chromothripsis scars the can- Chromosome mis-segregation during cer genome with localized DNA rearrangements that frequently generate exten- cell division frequently produces small nuclear structures called micronuclei, sive copy number alterations, oncogenic gene fusion products, and/or tumor which are prone to irreversible nuclear suppressor gene inactivation. Here we review emerging mechanisms underly- envelope disruption during interphase ing chromothripsis with a focus on the contribution of cell division errors and impaired nucleocytoplasmic compartmentalization. caused by centromere dysfunction. Micronucleated chromosomes accu- mulate extensive DNA damage and Hidden in Plain Sight: Chromothripsis in the Cancer Genome are susceptible to shattering during The karyotypes of cancer cells are often remarkably complex – littered not only with mutations the next mitosis, generating multiple, distinct DNA fragments. 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 Chromosome fragments are reas- most tumors, yet its role as a cause or consequence of cancer development remains under sembled by DNA double-strand break debate [1,2]. Structural aberrations and gross rearrangements alter the linear organization of repair to form a derivative chromosome. chromosomes, and in some instances can directly drive tumorigenesis. The Philadelphia chromosome in chronic myelogenous leukemia is the classic example [3], involving a translo- Chromatin bridges trapped between cation between chromosomes 9 and 22 to generate an oncogenic gene fusion product that can daughter cells are attacked by a cyto- be effectively targeted by clinical therapeutics [4]. plasmic nuclease (three-prime repair exonuclease 1; TREX1) during inter- phase to generate DNA breaks and Although it appears firmly established that tumorigenesis develops through the gradual and focal chromothripsis. sequential accumulation of genetic and/or epigenetic changes [5], recent cancer genome sequencing efforts challenged this dogmatic view by identifying several new classes of mutational processes that form simultaneously in a single burst. Adapted from the age-old theory in evolution, the paradigm-shifting concept of punctuated equilibrium (see Glossary) 1 Ludwig Institute for Cancer has now been applied toward our understanding of cancer progression models, as recently Research, Department of Cellular and Molecular Medicine, University of described in the renewed context of pancreatic cancer [6]. These punctuated events currently California at San Diego, La Jolla, CA include alterations such as kataegis (regions of clustered hypermutation) [7,8] and chromo- 92093, USA plexy (serial rearrangements linking multiple chromosomes) [9] À the underlying bases of which are not well understood. *Correspondence: [email protected] (P. Ly) and chromothripsis Among the most striking examples of punctuated equilibrium is (a Greek [email protected] ‘ ’ neologism for chromosome shattering ), in which tens to hundreds of structural (D.W. Cleveland). Trends in Cell Biology, December 2017, Vol. 27, No. 12 http://dx.doi.org/10.1016/j.tcb.2017.08.005 917 © 2017 Elsevier Ltd. All rights reserved. rearrangements are rapidly acquired within a short timeframe [10]. These complex rearrange- Glossary ments are curiously restricted to one or a few chromosomes, with breakpoints scattered across Acentric: a chromosome, or an entire chromosomal axis or clustered within a specific arm or region. Such alterations were fragment of a chromosome, that lacks an active centromere. predicted to form de novo from massive DNA damage and repair events, leading to a derivative Centromere: a specialized region on chromosome that shares little resemblance to its original configuration. The characteristic each chromosome designated for mutation signature for chromothripsis [11] has now been detected in a broad spectrum of assembly of the kinetochore and fi cancers, and of particular interest, at high frequency in specific tumor types – including bone, whose unique position is identi ed and maintained epigenetically. blood, and brain cancers [6,12–17]. Although the majority of chromothripsis cases occur Chromoanagenesis: a catch-all somatically, inherited forms of germline chromothripsis have also been documented [18]. term that encompasses catastrophic Additionally, similar types of complex rearrangements have been reported in individuals with mutational processes involving one or a few chromosomes, independent developmental and/or cognitive disorders, which appear to be caused by DNA replication of the precise mechanisms; included errors [19] in a process termed chromoanasynthesis. The catchall phrase chromoana- here are chromothripsis and genesis (Greek for ‘to be reborn’) has been coined [20] to encompass all the possible types of chromoanasynthesis, which arise localized and complex chromosomal rearrangements in human genomes irrespective of their through distinct mechanisms. Chromoanasynthesis: complex underlying mechanism of formation. rearrangements arising from the defective replication of a single or If chromothripsis causes such drastic changes in chromosome structure and occurs frequently few chromosomes. in some cancers, why had it not been discovered prior to 2011? Several types of large structural Chromoplexy: a series of chained, complex rearrangements frequently rearrangements, such as gross translocations, can be easily identified by routine cytogenetic involving five or more chromosomes. methodologies involving chromosome-banding patterns or fluorescent in situ hybridization Chromothripsis: complex (FISH). However, submicroscopic structural variations in the range of kilobase to even mega- rearrangements arising from the base rearrangements or more complex abnormalities, such as chromothripsis, can easily catastrophic shattering of a single or few chromosomes. escape recognition. Thus, initially missed by microscopy-based approaches, the recent advent Dicentric: a chromosome harboring of higher resolution next-generation DNA sequencing technologies enabled Stephens et al. [10] two active centromeres. to identify and resolve the complexity of rearrangements characterizing chromothripsis in Double minute (DM) cancer genomes. chromosome: circular and replication-competent extrachromosomal DNA elements The highly localized and complex nature of chromothripsis initially puzzled both cell biologists that accumulate and amplify multiple and cancer geneticists, leading to a spectrum of proposed hypotheses for the underlying gene copies that drive high levels of expression. mechanisms [10,20–23]. Considering that the rearrangements are often restricted to a single Kataegis: clusters of focal chromosome, it was strongly suspected that the affected chromosome must have been hypermutation preferentially favoring spatially isolated from the remaining genome, even if only for a transient period. DNA damage cytosine substitutions. in the form of double-strand breaks (DSBs) resulting in chromosome breakage is also likely Micronucleus: small, nuclear structures that encapsulate mis- involved followed by one or more mechanisms of error-prone DNA repair to produce the segregated chromosomes and are resulting rearrangements [10]. Many key aspects regarding the cellular mechanisms have spatially isolated from the main emerged over the last 5 years, including evidence supporting a role of cell division errors in the nucleus. shattering of an initially mis-segregated chromosome [24–26]. In this review, we cover recent Micronuclear envelope disruption: irreversible rupture of the insights into the mechanisms of chromothripsis with a particular focus on the role of mitotic nuclear envelope surrounding a errors driven by centromere dysfunction. We also highlight a number of outstanding micronucleus that causes abrupt loss questions. of nucleocytoplasmic partitioning and terminates micronuclear function. Non-homologous end joining: a Chromothripsis Driving Tumorigenesis major form of DNA DSB repair How does chromothripsis contribute to cancer development? The simultaneous formation of a whereby two damaged ends multiple alterations through chromothripsis can lead to the acquisition of one or more selective undergoes direct ligation. advantages (Figure 1A). Because chromothripsis can result in both the loss of DNA segments Punctuated equilibrium: a long- standing theory in evolutionary and the formation of de novo rearrangements, two obvious culprits are the disruption of tumor biology with recent