Positional stability of single double-strand breaks in mammalian cells.
Formation of cancerous translocations requires the illegitimate joining of chromosomes containing double-strand breaks (DSBs). It is unknown how broken chromosome ends find their translocation partners within the cell nucleus. Here, we have visualized and quantitatively analysed the dynamics of single DSBs in living mammalian cells. We demonstrate that broken ends are positionally stable and unable to roam the cell nucleus. Immobilization of broken chromosome ends requires the DNA-end binding protein Ku80, but is independent of DNA repair factors, H2AX, the MRN complex and the cohesion complex. DSBs preferentially undergo translocations with neighbouring chromosomes and loss of local positional constraint correlates with elevated genomic instability. These results support a contact-first model in which chromosome translocations predominantly form among spatially proximal DSBs.
Soutoglou
Evi
E
National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Dorn
Jonas F
JF
Sengupta
Kundan
K
Jasin
Maria
M
Nussenzweig
Andre
A
Ried
Thomas
T
Danuser
Gaudenz
G
Misteli
Tom
T
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D002875:Chromosomes / Q000235:genetics; D004247:DNA / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics; D006657:Histones / Q000235:genetics; D000072200:Ku Autoantigen; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*; D000097722:Cohesins
D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D004268:DNA-Binding Proteins; D006657:Histones; D000072200:Ku Autoantigen; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D000097722:Cohesins; C000606510:Xrcc6 protein, mouse; C475961:gamma-H2AX protein, mouse