DNA-Damage Response during Mitosis Induces Whole-Chromosome Missegregation
Samuel F. Bakhoum,Samuel F. Bakhoum,Lilian Kabeche,John P. Murnane,Bassem I. Zaki,Duane A. Compton +5 more
Reads0
Chats0
TLDR
It is shown that when DNA damage is induced during mitosis, the DDR unexpectedly induces errors in the segregation of entire chromosomes, thus linking structural and numerical chromosomal instabilities.Abstract:
Many cancers display both structural (s-CIN) and numerical (w-CIN) chromosomal instabilities. Defective chromosome segregation during mitosis has been shown to cause DNA damage that induces structural rearrangements of chromosomes (s-CIN). In contrast, whether DNA damage can disrupt mitotic processes to generate whole chromosomal instability (w-CIN) is unknown. Here we show that activation of the DNA damage response (DDR) during mitosis selectively stabilizes kinetochore-microtubule (k-MT) attachments to chromosomes through Aurora-A and Plk1 kinases, thereby increasing the frequency of lagging chromosomes during anaphase. Inhibition of DDR proteins, ATM or Chk2, abolishes the effect of DNA damage on k-MTs and chromosome segregation, whereas activation of the DDR in the absence of DNA damage is sufficient to induce chromosome segregation errors. Finally, inhibiting the DDR during mitosis in cancer cells with persistent DNA damage suppresses inherent chromosome segregation defects. Thus, DDR during mitosis inappropriately stabilizes k-MTs creating a link between s-CIN and w-CIN.read more
Citations
More filters
Journal ArticleDOI
Phagocytosis checkpoints as new targets for cancer immunotherapy.
TL;DR: An improved understanding of the tumour-intrinsic processes that inhibit essential immune surveillance processes, such as phagocytosis and innate immune sensing, could pave the way for the development of highly effective combination immunotherapy strategies that modulate both innate and adaptive antitumour immune responses.
Journal ArticleDOI
The multifaceted role of chromosomal instability in cancer and its microenvironment
TL;DR: These multipronged effects distinguish CIN as a central driver of tumor evolution and as a genomic source for the crosstalk between the tumor and its microenvironment, in the course of immune editing and evasion.
Journal ArticleDOI
Cell cycle control in cancer.
TL;DR: A detailed analysis of cell cycle control mechanisms and their role in cancer can be found in this article, where the authors reveal how these dependencies can be best exploited in cancer treatment and how to best exploit these dependencies.
Journal ArticleDOI
Aneuploidy and chromosomal instability in cancer: a jackpot to chaos
TL;DR: Findings suggest that the relationship between CIN, aneuploidy and cancer is more complex than what was previously anticipated and a working hypothesis is proposed to reconcile the conflicting observations regarding the role of aneuPLoidsy and CIN in tumorigenesis.
Journal ArticleDOI
Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids.
Ana C.F. Bolhaqueiro,Bas Ponsioen,Bjorn Bakker,Sjoerd J Klaasen,Emre Kucukkose,Richard H. van Jaarsveld,Judith Vivié,Ingrid Verlaan-Klink,Nizar Hami,Diana C.J. Spierings,Nobuo Sasaki,Devanjali Dutta,Sylvia F. Boj,Robert G.J. Vries,Peter M. Lansdorp,Peter M. Lansdorp,Marc van de Wetering,Alexander van Oudenaarden,Hans Clevers,Onno Kranenburg,Floris Foijer,Hugo J. Snippert,Geert J. P. L. Kops +22 more
TL;DR: It is concluded that ongoing CIN is common in colorectal cancer organoids, and proposed that CIN levels and the tolerance for mitotic errors shape aneuploidy landscapes and karyotype heterogeneity.
References
More filters
Journal ArticleDOI
Replication stress links structural and numerical cancer chromosomal instability (vol 494, pg 492, 2013)
Rebecca A. Burrell,Sarah E. McClelland,David Endesfelder,Petra Groth,Marie-Christine Weller,Nadeem Shaikh,Enric Domingo,Nnennaya Kanu,Sally M. Dewhurst,Eva Grönroos,Su Kit Chew,Andrew Rowan,Arne Schenk,Michal Sheffer,Michael Howell,Maik Kschischo,Axel Behrens,Thomas Helleday,Jiri Bartek,Ian Tomlinson,Charles Swanton +20 more
Journal ArticleDOI
Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine
TL;DR: Addition of reversine to dividing cells ejects Mad1 and the RZZ complex from unattached kinetochores and prevents resolution of incorrect chromosome–microtubule attachments.
Journal ArticleDOI
Genome stability is ensured by temporal control of kinetochore–microtubule dynamics
TL;DR: It is shown that two microtubule-depolymerizing kinesins, Kif2b and MCAK, stimulate kinetochore–microtubule dynamics during distinct phases of mitosis to correct mal-orientations, establishing a causal relationship between deregulation of kinetechore– microtubules dynamics and chromosomal instability.
Book
Clinical Radiation Oncology
TL;DR: Radiobiology: Biologic Basis of Radiation Oncology, Molecular/Cellular Biology, and Other Cancer Disciplines: Surgery Principles.
Journal ArticleDOI
DNA damage signaling in response to double-strand breaks during mitosis
TL;DR: Dividing cells can sense DNA damage and initiate a primary response, but repair isn’t completed until the cells enter G1, and that’s when the cell enters G1 and begins to repair itself.
Related Papers (5)
Replication stress links structural and numerical cancer chromosomal instability
Rebecca A. Burrell,Sarah E. McClelland,David Endesfelder,Petra Groth,Marie-Christine Weller,Nadeem Shaikh,Enric Domingo,Nnennaya Kanu,Sally M. Dewhurst,Eva Grönroos,Su Kit Chew,Andrew Rowan,Arne Schenk,Michal Sheffer,Michael Howell,Maik Kschischo,Axel Behrens,Thomas Helleday,Jiri Bartek,Ian Tomlinson,Charles Swanton +20 more