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
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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
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References
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DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
TL;DR: It is shown that ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 that is contained within the previously described ‘FAT’ domain.
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Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM.
Ian Hickson,Yan Zhao,Caroline Richardson,Sharon J. Green,Niall M. B. Martin,Alisdair I. Orr,Philip Michael Reaper,Stephen P. Jackson,Nicola J. Curtin,Graeme C. M. Smith +9 more
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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.
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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
TL;DR: Evidence for impaired replication fork progression and increased DNA replication stress in CIN+ colorectal cancer (CRC) cells relative to CIN− CRC cells is found, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis.
Journal ArticleDOI
Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery
Libor Macůrek,Arne Lindqvist,Daniel Lim,Michael A. Lampson,Rob Klompmaker,Raimundo Freire,Christophe Clouin,Stephen S. Taylor,Michael B. Yaffe,René H. Medema +9 more
TL;DR: It is demonstrated that the initial activation of PLK1 is a primary function of aurora A, and that Bora/aurora-A-dependent phosphorylation is a prerequisite for PLK 1 to promote mitotic entry after a checkpoint-dependent arrest.
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