Chromothripsis drives the evolution of gene amplification in cancer.
Ofer Shoshani,Simon F. Brunner,Rona Yaeger,Peter Ly,Yael Nechemia-Arbely,Dong Hyun Kim,Rongxin Fang,Guillaume A. Castillon,Miao Yu,Julia S. Z. Li,Ying Sun,Mark H. Ellisman,Bing Ren,Peter J. Campbell,Peter J. Campbell,Don W. Cleveland +15 more
TLDR
In this paper, the authors 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 through mechanisms that depend on poly(ADP-ribose) polymerases (PARP) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).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.read more
Citations
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Oncogene expression from extrachromosomal DNA is driven by copy number amplification and does not require spatial clustering in glioblastoma stem cells
Karin Purshouse,Elias T. Friman,Shelagh Boyle,Pooran Singh Dewari,Vivien Grant,Alhafidz Hamdan,Gillian Morrison,Paul Brennan,Sjoerd Viktor Beentjes,Steven M. Pollard,Wendy A. Bickmore +10 more
TL;DR: It is suggested that is the increased copy number of oncogene-harbouring ecDNA that primarily drives high levels ofoncogene transcription, rather than specific interactions of ecDNA with the cellular transcriptional machinery.
Journal ArticleDOI
Micronuclei from misaligned chromosomes that satisfy the spindle assembly checkpoint in cancer cells
Ana Margarida Gomes,Bernardo Orr,Marco Novais-Cruz,Filipe de Sousa,Joana Macário-Monteiro,Carolina Lemos,Cristina Ferrás,Helder Maiato +7 more
TL;DR: In this article , the authors investigated how human cells respond to chromosome alignment defects of distinct molecular nature by following the fate of live HeLa cells after RNAi-mediated depletion of 125 proteins previously implicated in chromosome alignment.
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Therapy Induced Genome Chaos: A Novel Mechanism of Rapid Cancer Drug Resistance
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A unifying model for extrachromosomal circular DNA load in eukaryotic cells.
TL;DR: In this article , a unifying 5-factor model for conceptualizing the eccDNA load of a eukaryotic cell is proposed, emphasizing formation, replication, segregation, selection and elimination.
Journal ArticleDOI
CRISPRthripsis: The Risk of CRISPR/Cas9-induced Chromothripsis in Gene Therapy
TL;DR: The factors influencing CRISPR/Cas9-induced chromothripsis and its outcomes are discussed, the tools to characterize these events and strategies to minimize them are discussed.
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Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development
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TL;DR: It is found that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis, which has important implications for the origins of genomic remodeling and temporal emergence of cancer.
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