title: Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations.
abstract: Various types of chromosomal aberrations, including numerical (aneuploidy) and structural (e.g., translocations, deletions), are commonly found in human tumors and are linked to tumorigenesis. Aneuploidy is a direct consequence of chromosome segregation errors in mitosis, whereas structural aberrations are caused by improperly repaired DNA breaks. Here, we demonstrate that chromosome segregation errors can also result in structural chromosome aberrations. Chromosomes that missegregate are frequently damaged during cytokinesis, triggering a DNA double-strand break response in the respective daughter cells involving ATM, Chk2, and p53. We show that these double-strand breaks can lead to unbalanced translocations in the daughter cells. Our data show that segregation errors can cause translocations and provide insights into the role of whole-chromosome instability in tumorigenesis.
authors.affiliation: Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, Netherlands.
authors.forename: Aniek
authors.initials: A
authors.lastname: Janssen
authors.forename: Marja
authors.initials: M
authors.lastname: van der Burg
authors.forename: Karoly
authors.initials: K
authors.lastname: Szuhai
authors.forename: Geert J P L
authors.initials: GJ
authors.lastname: Kops
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D020090:Chromosome Segregation; D048749:Cytokinesis; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines / Q000494:pharmacology; D013871:Thiones / Q000494:pharmacology; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C495901:TP53 protein, human; C498301:TP53BP1 protein, human; D013871:Thiones; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C400223:monastrol; D064447:Checkpoint Kinase 2; D011505:Protein-Tyrosine Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human