Centromere-localized breaks indicate the generation of DNA damage by the mitotic spindle.
Most carcinomas present some form of chromosome instability in combination with spindle defects. Numerical instability is likely caused by spindle aberrations, but the origin of breaks and translocations remains elusive. To determine whether one mechanism can bring about both types of instability, we studied the relationship between DNA damage and spindle defects. Although lacking apparent repair defects, primary Dido mutant cells formed micronuclei containing damaged DNA. The presence of centromeres showed that micronuclei were caused by spindle defects, and cell cycle markers showed that DNA damage was generated during mitosis. Although the micronuclei themselves persisted, the DNA damage within was repaired during S and G2 phases. DNA breaks in Dido mutant cells regularly colocalized with centromeres, which were occasionally distorted. Comparable defects were found in APC mutant cell lines, an independent system for spindle defects. On the basis of these results, we propose a model for break formation in which spindle defects lead to centromere shearing.
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco Campus, 28049 Madrid, Spain.
Astrid Alonso
AA
Guerrero
Mercedes Cano
MC
Gamero
Varvara
V
Trachana
Agnes
A
Fütterer
Cristina
C
Pacios-Bras
Nuria Panadero
NP
Díaz-Concha
Juan Cruz
JC
Cigudosa
Carlos
C
Martínez-A
Karel H M
KH
van Wely
D000818:Animals; D002478:Cells, Cultured; D002503:Centromere; D004249:DNA Damage; D004260:DNA Repair; D006657:Histones / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D008941:Spindle Apparatus
D006657:Histones