Nuclear envelope assembly defects link mitotic errors to chromothripsis
Shiwei Liu,Mijung Kwon,Mark Mannino,Mark Mannino,Nachen Yang,Fioranna Renda,Alexey Khodjakov,David Pellman,David Pellman +8 more
Reads0
Chats0
TLDR
It is shown that spindle microtubules block assembly of NPCs and other non-core nuclear envelope proteins on lagging chromosomes, causing an irreversible defect in nuclear envelope assembly, which leads to spontaneous envelope disruption of micronuclei and subsequent genome instability.Abstract:
Defects in the architecture or integrity of the nuclear envelope are associated with a variety of human diseases1. Micronuclei, one common nuclear aberration, are an origin for chromothripsis2, a catastrophic mutational process that is commonly observed in cancer3–5. Chromothripsis occurs after micronuclei spontaneously lose nuclear envelope integrity, which generates chromosome fragmentation6. Disruption of the nuclear envelope exposes DNA to the cytoplasm and initiates innate immune proinflammatory signalling7. Despite its importance, the basis of the fragility of the micronucleus nuclear envelope is not known. Here we show that micronuclei undergo defective nuclear envelope assembly. Only ‘core’ nuclear envelope proteins8,9 assemble efficiently on lagging chromosomes, whereas ‘non-core’ nuclear envelope proteins8,9, including nuclear pore complexes (NPCs), do not. Consequently, micronuclei fail to properly import key proteins that are necessary for the integrity of the nuclear envelope and genome. We show that spindle microtubules block assembly of NPCs and other non-core nuclear envelope proteins on lagging chromosomes, causing an irreversible defect in nuclear envelope assembly. Accordingly, experimental manipulations that position missegregated chromosomes away from the spindle correct defective nuclear envelope assembly, prevent spontaneous nuclear envelope disruption, and suppress DNA damage in micronuclei. Thus, during mitotic exit in metazoan cells, chromosome segregation and nuclear envelope assembly are only loosely coordinated by the timing of mitotic spindle disassembly. The absence of precise checkpoint controls may explain why errors during mitotic exit are frequent and often trigger catastrophic genome rearrangements4,5. The mitotic spindle prevents normal nuclear envelope assembly on missegregated chromosomes, leading to spontaneous envelope disruption of micronuclei and subsequent genome instability.read more
Citations
More filters
Journal ArticleDOI
Inflammatory microenvironment remodelling by tumour cells after radiotherapy.
Martin McLaughlin,Emmanuel C Patin,Malin Pedersen,Anna Wilkins,Magnus T. Dillon,Magnus T. Dillon,Alan Melcher,Alan Melcher,Kevin J. Harrington,Kevin J. Harrington +9 more
TL;DR: How radiotherapy, through its immunomodulating effects, represents a promising combination partner with ICIs and how DNA damage response inhibitors in combination with radiotherapy may be used to further augment this approach are described.
Journal ArticleDOI
Mechanisms generating cancer genome complexity from a single cell division error
Neil T. Umbreit,Neil T. Umbreit,Cheng-Zhong Zhang,Luke D. Lynch,Logan J. Blaine,Anna M. Cheng,Anna M. Cheng,Richard W. Tourdot,Lili Sun,Hannah Almubarak,Kim Judge,Thomas J. Mitchell,Thomas J. Mitchell,Alexander Spektor,David Pellman,David Pellman +15 more
TL;DR: This work recreated essential steps of the BFB cycle in a defined system, enabling mechanistic studies and determination of the immediate and long-term genomic consequences of bridge formation, suggesting a unifying model for how cancer-associated defects in nuclear architecture is handled.
Journal ArticleDOI
Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing.
Mitchell L. Leibowitz,Stamatis Papathanasiou,Phillip A. Doerfler,Logan J. Blaine,Lili Sun,Yu Yao,Cheng-Zhong Zhang,Mitchell J. Weiss,David Pellman,David Pellman +9 more
TL;DR: In this paper, it was shown that CRISPR-Cas9 editing generates structural defects of the nucleus, micronuclei and chromosome bridges, which initiate a mutational process called chromothripsis.
Posted ContentDOI
Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing
Mitchell L. Leibowitz,Mitchell L. Leibowitz,Stamatis Papathanasiou,Phillip A. Doerfler,Logan J. Blaine,Yu Yao,Cheng-Zhong Zhang,Mitchell J. Weiss,David Pellman,David Pellman +9 more
TL;DR: It is shown that CRISPR-Cas9-mediated DNA breaks generate abnormal nuclear structures—micronuclei and chromosome bridges—that trigger chromothripsis, an on-target toxicity that may be minimized by cell manipulation protocols or screening but cannot be completely avoided in many genome editing applications.
Journal ArticleDOI
Regulation of cGAS- and RLR-mediated immunity to nucleic acids
Andrea Ablasser,Sun Hur +1 more
TL;DR: This Review addresses the emerging literature on regulation of the sensing of cytosolic DNA and RNA via cGAS and RLRs and offers a rich and largely unexplored source for new therapeutic targets.
References
More filters
Journal ArticleDOI
Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development
Philip J. Stephens,Christopher Greenman,Beiyuan Fu,Fengtang Yang,Graham R. Bignell,Laura Mudie,Erin Pleasance,King Wai Lau,David Beare,Lucy Stebbings,Stuart McLaren,Meng-Lay Lin,David J. McBride,Ignacio Varela,Serena Nik-Zainal,Catherine Leroy,Mingming Jia,Andrew Menzies,Adam Butler,Jon W. Teague,Michael A. Quail,John Burton,Harold Swerdlow,Nigel P. Carter,Laura Morsberger,Christine A. Iacobuzio-Donahue,George A. Follows,Anthony R. Green,Adrienne M. Flanagan,Adrienne M. Flanagan,Michael R. Stratton,P. Andrew Futreal,Peter J. Campbell,Peter J. Campbell +33 more
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.
Journal ArticleDOI
Three-Dimensional Resolution Doubling in Wide-Field Fluorescence Microscopy by Structured Illumination
Mats G. L. Gustafsson,Lin Shao,Peter M. Carlton,C. J. Rachel Wang,Inna N. Golubovskaya,W. Zacheus Cande,David A. Agard,David A. Agard,John W. Sedat +8 more
TL;DR: This work describes how spatially structured illumination microscopy can be applied in three dimensions to double the axial as well as the lateral resolution, with true optical sectioning, and has produced the first light microscopy images of the synaptonemal complex in which the lateral elements are clearly resolved.
Journal ArticleDOI
DNA breaks and chromosome pulverization from errors in mitosis
Karen Crasta,Neil J. Ganem,Neil J. Ganem,Regina Dagher,Regina Dagher,Alexandra B. Lantermann,Elena Ivanova,Yunfeng Pan,Luigi Nezi,Alexei Protopopov,Dipanjan Chowdhury,David Pellman,David Pellman +12 more
TL;DR: A mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei is identified, which potentially lead to mutations and chromosome rearrangements that can integrate into the genome.
Journal ArticleDOI
Nuclear envelope rupture and repair during cancer cell migration
Celine Denais,Rachel M. Gilbert,Philipp Isermann,Alexandra L. McGregor,Mariska te Lindert,Bettina Weigelin,Patricia M. Davidson,Peter Friedl,Peter Friedl,Katarina Wolf,Jan Lammerding +10 more
TL;DR: Investigation of mammalian tumor cell migration in confining microenvironments in vitro and in vivo indicates that cell migration incurs substantial physical stress on the NE and its content and requires efficient NE and DNA damage repair for cell survival.
Journal ArticleDOI
Chromothripsis from DNA damage in micronuclei
Cheng-Zhong Zhang,Alexander Spektor,Hauke Cornils,Joshua M. Francis,Emily K. Jackson,Shiwei Liu,Matthew Meyerson,David Pellman +7 more
TL;DR: It is demonstrated that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis.
Related Papers (5)
cGAS surveillance of micronuclei links genome instability to innate immunity
Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development
Philip J. Stephens,Christopher Greenman,Beiyuan Fu,Fengtang Yang,Graham R. Bignell,Laura Mudie,Erin Pleasance,King Wai Lau,David Beare,Lucy Stebbings,Stuart McLaren,Meng-Lay Lin,David J. McBride,Ignacio Varela,Serena Nik-Zainal,Catherine Leroy,Mingming Jia,Andrew Menzies,Adam Butler,Jon W. Teague,Michael A. Quail,John Burton,Harold Swerdlow,Nigel P. Carter,Laura Morsberger,Christine A. Iacobuzio-Donahue,George A. Follows,Anthony R. Green,Adrienne M. Flanagan,Adrienne M. Flanagan,Michael R. Stratton,P. Andrew Futreal,Peter J. Campbell,Peter J. Campbell +33 more