title: DNA-damage response during mitosis induces whole-chromosome missegregation.
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, the DDR during mitosis inappropriately stabilizes k-MTs, creating a link between s-CIN and w-CIN.
  
  
  CONCLUSIONS
  The genome-protective role of the DDR depends on its ability to delay cell division until damaged DNA can be fully repaired. Here, we show 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.
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. samuel.bakhoum@gmail.com duane.a.compton@dartmouth.edu.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Bakhoum
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Lilian
authors.initials: L
authors.lastname: Kabeche
authors.affiliation: Department of Radiation Oncology, University of California, San Francisco, San Francisco, California.
authors.forename: John P
authors.initials: JP
authors.lastname: Murnane
authors.affiliation: Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Section of Radiation Oncology, Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Bassem I
authors.initials: BI
authors.lastname: Zaki
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. samuel.bakhoum@gmail.com duane.a.compton@dartmouth.edu.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Compton
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D064096:Aurora Kinase A / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D004249:DNA Damage; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D064096:Aurora Kinase A; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C576324:ATM protein, human; C576917:AURKA protein, human; C578634:CHEK2 protein, human
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