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Open accessJournal ArticleDOI: 10.1038/S41586-020-03064-Z

Chromothripsis drives the evolution of gene amplification in cancer.

04 Mar 2021-Nature (Nature Publishing Group)-Vol. 591, Iss: 7848, pp 137-141
Abstract: Focal chromosomal amplification contributes to the initiation of cancer by mediating overexpression of oncogenes1–3, and to the development of cancer therapy resistance by increasing the expression of genes whose action diminishes the efficacy of anti-cancer drugs. Here we used whole-genome sequencing of clonal cell isolates that developed chemotherapeutic resistance to show that chromothripsis is a major driver of circular extrachromosomal DNA (ecDNA) amplification (also known as double minutes) through mechanisms that depend on poly(ADP-ribose) polymerases (PARP) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Longitudinal analyses revealed that a further increase in drug tolerance is achieved by structural evolution of ecDNAs through additional rounds of chromothripsis. In situ Hi-C sequencing showed that ecDNAs preferentially tether near chromosome ends, where they re-integrate when DNA damage is present. Intrachromosomal amplifications that formed initially under low-level drug selection underwent continuing breakage–fusion–bridge cycles, generating amplicons more than 100 megabases in length that became trapped within interphase bridges and then shattered, thereby producing micronuclei whose encapsulated ecDNAs are substrates for chromothripsis. We identified similar genome rearrangement profiles linked to localized gene amplification in human cancers with acquired drug resistance or oncogene amplifications. We propose that chromothripsis is a primary mechanism that accelerates genomic DNA rearrangement and amplification into ecDNA and enables rapid acquisition of tolerance to altered growth conditions. Chromothripsis—a process during which chromosomes are ‘shattered’—drives the evolution of gene amplification and subsequent drug resistance in cancer cells.

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Topics: Chromothripsis (64%), Amplicon (54%), Extrachromosomal DNA (51%) ... read more

44 results found

Journal ArticleDOI: 10.1016/J.CEB.2021.01.004
Abstract: Micronuclei are small membrane-bounded compartments with a DNA content encapsulated by a nuclear envelope and spatially separated from the primary nucleus. Micronuclei have long been linked to chromosome instability, genome rearrangements, and mutagenesis. They are frequently found in cancers, during senescence, and after genotoxic stress. Compromised integrity of the micronuclear envelope delays or disrupts DNA replication, inhibits DNA repair, and exposes micronuclear DNA directly to cytoplasm. Micronuclei play a central role in tumorigenesis, with micronuclear DNA being a source of complex genome rearrangements (including chromothripsis) and promoting a cyclic GMP–AMP synthase (cGAS)-mediated cellular immune response that may contribute to cancer metastasis. Here, we discuss recent findings on how micronuclei are generated, what the consequences are, and what cellular mechanisms can be applied to protect against micronucleation.

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Topics: Chromothripsis (59%), DNA repair (56%), Micronucleus test (53%) ... read more

8 Citations

Open accessJournal ArticleDOI: 10.1016/J.SEMCDB.2021.06.009
Abstract: The spindle assembly checkpoint (SAC) is a surveillance mechanism that promotes accurate chromosome segregation in mitosis. The checkpoint senses the attachment state of kinetochores, the proteinaceous structures that assemble onto chromosomes in mitosis in order to mediate their interaction with spindle microtubules. When unattached, kinetochores generate a diffusible inhibitor that blocks the activity of the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase required for sister chromatid separation and exit from mitosis. Work from the past decade has greatly illuminated our understanding of the mechanisms by which the diffusible inhibitor is assembled and how it inhibits the APC/C. However, less is understood about how SAC proteins are recruited to kinetochores in the absence of microtubule attachment, how the kinetochore catalyzes formation of the diffusible inhibitor, and how attachments silence the SAC at the kinetochore. Here, we summarize current understanding of the mechanisms that activate and silence the SAC at kinetochores and highlight open questions for future investigation.

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Topics: Kinetochore (62%), Spindle checkpoint (62%), Spindle apparatus (58%) ... read more

6 Citations

Journal ArticleDOI: 10.1038/S41568-021-00377-7
Gene Koh1, Andrea Degasperi1, Xueqing Zou1, Sophie Momen1  +1 moreInstitutions (1)
Abstract: Whole-genome sequencing has brought the cancer genomics community into new territory. Thanks to the sheer power provided by the thousands of mutations present in each patient's cancer, we have been able to discern generic patterns of mutations, termed 'mutational signatures', that arise during tumorigenesis. These mutational signatures provide new insights into the causes of individual cancers, revealing both endogenous and exogenous factors that have influenced cancer development. This Review brings readers up to date in a field that is expanding in computational, experimental and clinical directions. We focus on recent conceptual advances, underscoring some of the caveats associated with using the mutational signature frameworks and highlighting the latest experimental insights. We conclude by bringing attention to areas that are likely to see advancements in clinical applications.

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5 Citations

Journal ArticleDOI: 10.1016/J.SEMCANCER.2021.06.007
Jinsong Liu1Institutions (1)
Abstract: The "life code" theory postulates that egg cells, which are giant, are the first cells in reproduction and that damaged or aged giant somatic cells are the first cells in tumorigenesis. However, the hereditary basis for giant cells remains undefined. Here I propose that stress-induced genomic reorganization proposed by Nobel Laureate Barbara McClintock may represent the underlying heredity for giant cells, referred to as McClintock's heredity. Increase in cell size may serve as a response to environmental stress via switching proliferative mitosis to intranuclear replication for reproduction. Intranuclear replication activates McClintock's heredity to reset the genome following fertilization for reproduction or restructures the somatic genome for neoplastic transformation via formation of polyploid giant cancer cells (PGCCs). The genome-based McClintock heredity functions together with gene-based Mendel's heredity to regulate the genomic stability at two different stages of life cycle or tumorigenesis. Thus, giant cells link McClintock's heredity to both early embryogenesis and tumor origin. Cycling change in cell size together with ploidy number switch may represent the most fundamental mechanism on how both germ and soma for coping with environmental stresses for the survival across the tree of life which evolved over millions of years on Earth.

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Topics: Neoplastic transformation (52%), Giant cell (52%), Heredity (51%)

5 Citations

Open accessPosted ContentDOI: 10.1101/2021.02.26.433009
26 Feb 2021-bioRxiv
Abstract: Summary Micronuclei are a hallmark of cancer and other human disorders and have recently been implicated in chromothripsis, a series of massive genomic rearrangements that may drive tumor evolution and progression. Here we show that Aurora B kinase mediates a surveillance mechanism that integrates error correction during anaphase with spatial control of nuclear envelope reformation to protect against micronuclei formation during human cell division. Using high-resolution live-cell imaging of human cancer and non-cancer cells we found that anaphase lagging chromosomes are often transient and rarely formed micronuclei. This strong bias against micronuclei formation relied on a midzone-based Aurora B phosphorylation gradient that assisted the mechanical transduction of spindle forces at the kinetochore-microtubule interface required for anaphase error correction, while delaying nuclear envelope reformation on lagging chromosomes, independently of microtubules. Our results uncover a new layer of protection against genomic instability and provide a strategy for the rational design of micronuclei-targeting therapies.

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Topics: Anaphase (63%), Aurora B kinase (56%), Chromothripsis (56%) ... read more

5 Citations


46 results found

Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTP324
Heng Li1, Richard Durbin1Institutions (1)
01 Jul 2009-Bioinformatics
Abstract: Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ~10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: Contact: [email protected]

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Topics: Hybrid genome assembly (54%), Sequence assembly (53%), 2 base encoding (52%) ... read more

35,234 Citations

Open accessJournal ArticleDOI: 10.1038/NMETH.2019
01 Jul 2012-Nature Methods
Abstract: Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.

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Topics: Software design (51%), Software (50%)

30,888 Citations

Open accessJournal ArticleDOI: 10.1016/J.CELL.2014.11.021
18 Dec 2014-Cell
Abstract: We use in situ Hi-C to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ∼10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs "facing" one another. The inactive X chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats.

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Topics: CTCF (55%), Chromatin Loop (53%), Chromosome conformation capture (51%) ... read more

4,386 Citations

Open accessJournal ArticleDOI: 10.1093/NAR/GKR218
Tomas Cermak1, Erin L. Doyle2, Michelle Christian2, Li-Li Wang2  +6 moreInstitutions (2)
Abstract: TALENs are important new tools for genome engineering. Fusions of transcription activator-like (TAL) effectors of plant pathogenic Xanthomonas spp. to the FokI nuclease, TALENs bind and cleave DNA in pairs. Binding specificity is determined by customizable arrays of polymorphic amino acid repeats in the TAL effectors. We present a method and reagents for efficiently assembling TALEN constructs with custom repeat arrays. We also describe design guidelines based on naturally occurring TAL effectors and their binding sites. Using software that applies these guidelines, in nine genes from plants, animals and protists, we found candidate cleavage sites on average every 35bp. Each of 15 sites selected from this set was cleaved in a yeast-based assay with TALEN pairs constructed with our reagents. We used two of the TALEN pairs to mutate HPRT1 in human cells and ADH1 in Arabidopsis thaliana protoplasts. Our reagents include a plasmid construct for making custom TAL effectors and one for TAL effector fusions to additional proteins of interest. Using the former, we constructed de novo a functional analog of AvrHah1 of Xanthomonas gardneri. The complete plasmid set is available through the non-profit repository AddGene

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2,026 Citations

Open accessJournal ArticleDOI: 10.1016/J.CELL.2010.11.055
07 Jan 2011-Cell
Abstract: SUMMARY Cancer is driven by somatically acquired point mutations and chromosomal rearrangements, conventionally thought to accumulate gradually over time. Using next-generation sequencing, we characterize aphenomenon, which we term chromothripsis, whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. Rearrangements involving one or a few chromosomes crisscross back and forth across involved regions, generating frequent oscillations between two copy number states. These genomic hallmarks are highly improbable if rearrangements accumulate over time and instead imply that nearly all occur during a single cellular catastrophe. The stamp of chromothripsis can be seen in at least 2%–3% of all cancers, across many subtypes, and is present in � 25% of bone cancers. We find that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis. This phenomenon has important implications for the origins of genomic remodeling and temporal emergence of cancer.

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Topics: Chromothripsis (67%), Gene rearrangement (53%)

1,874 Citations

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