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
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Spindle assembly checkpoint activation and silencing at kinetochores
TL;DR: In this article, the authors summarize current understanding of the mechanisms that activate and silence the SAC at kinetochores and highlight open questions for future investigation, including how SAC proteins are recruited to SAC in the absence of microtubule attachment.
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Mutational signatures: emerging concepts, caveats and clinical applications.
TL;DR: In this article, the authors present a review of recent conceptual advances in the field of mutational signatures, highlighting some of the caveats associated with using the mutational signature frameworks and highlighting the latest experimental insights.
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Causes and consequences of micronuclei.
TL;DR: In this paper, the authors discuss how micronuclei are generated, what the consequences are, and what cellular mechanisms can be applied to protect against micronuclearation, with a focus on the effects of DNA degradation.
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Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities
Abrar Choudhury,Stephen T. Magill,Charlotte D. Eaton,Briana C. Prager,William C. Chen,Martha A. Cady,Kyounghee Seo,Calixto-Hope G Lucas,T. Casey-Clyde,Harish N. Vasudevan,S. John Liu,Javier Villanueva-Meyer,Tai Chung Lam,Jenny Kan-suen Pu,Lai-Fung Li,Gilberto K.K. Leung,Danielle L. Swaney,Michael Zhang,Jason Chan,Zhixin Qiu,Michael Martin,Matthew S. Susko,Steve Braunstein,Nancy Ann Oberheim Bush,Jessica Schulte,Nicholas Butowski,Penny K. Sneed,Mitchel S. Berger,Nevan J. Krogan,Arie Perry,T. J. Phillips,David A. Solomon,Joseph F. Costello,Michael P. McDermott,Jeremy N. Rich,David R. Raleigh +35 more
TL;DR: In this paper , DNA methylation profiling of 565 meningiomas highlights three groups associated with distinct molecular, clinical and therapeutic features: immune-enriched, hypermitotic and Merlin-intact meningus.
Journal ArticleDOI
Live-Cell Imaging Shows Uneven Segregation of Extrachromosomal DNA Elements and Transcriptionally Active Extrachromosomal DNA Hubs in Cancer
TL;DR: Henssen et al. as mentioned in this paper used the CRISPR-based ecTag method to evaluate the transfer of ecDNA genetic material from parental to offspring cells during mitosis, which revealed disjointed inheritance patterns, enabling rapid ecDNA accumulation in individual cells.
References
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DNA Sequence-Specific Binding of CENP-B Enhances the Fidelity of Human Centromere Function
Daniele Fachinetti,Joo Seok Han,Moira A. McMahon,Peter Ly,Amira Abdullah,Alex J. Wong,Don W. Cleveland +6 more
TL;DR: DNA sequence-dependent binding of CENP-B within α-satellite repeats is required to stabilize optimal centromeric levels of C ENP-C, and data demonstrate a DNA sequence-specific enhancement by CENp-B of the fidelity of epigenetically defined human centromere function.
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Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining
Peter Ly,Levi S. Teitz,Dong Hyun Kim,Ofer Shoshani,Helen Skaletsky,Daniele Fachinetti,David C. Page,Don W. Cleveland +7 more
TL;DR: An inducible Y centromere-selective inactivation strategy is developed by exploiting a CENP-A/histone H3 chimaera to directly examine the fate of missegregated chromosomes in otherwise diploid human cells, and initial errors in cell division can provoke further genomic instability through fragmentation of micronuclear DNAs coupled to NHEJ-mediated reassembly in the subsequent interphase.
Journal ArticleDOI
Extrachromosomal oncogene amplification in tumour pathogenesis and evolution.
TL;DR: The existence of extrachromosomal DNA (ecDNA) in cancer was first described decades ago, but recent reports of oncogene amplification on ecDNA have reinvigorated interest in this field.
Journal ArticleDOI
Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma
Ana C. deCarvalho,Hoon Kim,Laila M. Poisson,Mary E. Winn,Claudius Mueller,David Cherba,Julie Koeman,Sahil Seth,Alexei Protopopov,Michelle Madden Felicella,Siyuan Zheng,Asha S. Multani,Yongying Jiang,Jianhua Zhang,Do Hyun Nam,Do Hyun Nam,Emanuel F. Petricoin,Lynda Chin,Tom Mikkelsen,Roel G.W. Verhaak +19 more
TL;DR: Analysis of glioblastoma samples and derived neurospheres and Xenografts shows that chromosomal and extrachromosomal alterations often display divergent inheritance patterns during cell culture and xenografting, independently of chromosomal DNA alterations.
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The architecture and evolution of cancer neochromosomes.
Dale W. Garsed,Dale W. Garsed,Owen J. Marshall,Vincent Corbin,Vincent Corbin,Vincent Corbin,Arthur Hsu,Leon Di Stefano,Jan Schröder,Jan Schröder,Jason Li,Zhi-Ping Feng,Zhi-Ping Feng,Bo W. Kim,Mark Kowarsky,Ben Lansdell,Ross Brookwell,Ola Myklebost,Leonardo A. Meza-Zepeda,Andrew J. Holloway,Florence Pedeutour,K. H. Andy Choo,Michael A. Damore,Andrew J. Deans,Anthony T. Papenfuss,David Thomas,David Thomas,David Thomas +27 more
TL;DR: The dynamic mutational processes underlying the life history of a special form of cancer mutation are investigated, including amplification terminates, and the neochromosome core is stabilized in linear form by telomere capture.
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