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.centrosome | chromosome instability | double-strand break | H2A.X

Numerical and/or structural centrosome abnormalities have been correlated with most solid tumors and hematological malignancies. Tumorigenesis also is linked to defects in the mitotic or spindle assembly checkpoint, a key control mechanism that ensures accurate segregation of chromosomes during mitosis. We have reported that targeted disruption of the Dido gene causes a transplantable myelodysplastic/myeloproliferative disease in mice. Here, we report that Dido3, the largest splice variant of the Dido gene, is a centrosomeassociated protein whose disruption leads to supernumerary centrosomes, failure to maintain cellular mitotic arrest, and early degradation of the mitotic checkpoint protein BubR1. These aberrations result in enhanced aneuploidy in the Dido mutant cells. Dido gene malfunction thus is reported to be part of an impaired signaling cascade that results in a defective mitotic checkpoint, leading to chromosome instability.aneuploidy ͉ cell cycle ͉ genomic stability

No abstract

No abstract

Synapsis of homologous chromosomes is a key meiotic event, mediated by a large proteinaceous structure termed the synaptonemal complex. Here, we describe a role in meiosis for the murine death-inducer obliterator (Dido) gene. The Dido gene codes for three proteins that recognize trimethylated histone H3 lysine 4 through their amino-terminal plant homeodomain domain. DIDO3, the largest of the three isoforms, localizes to the central region of the synaptonemal complex in germ cells. DIDO3 follows the distribution of the central region protein SYCP1 in Sycp3-/- spermatocytes, which lack the axial elements of the synaptonemal complex. This indicates that synapsis is a requirement for DIDO3 incorporation. Interestingly, DIDO3 is missing from the synaptonemal complex in Atm mutant spermatocytes, which form synapses but show persistent trimethylation of histone H3 lysine 4. In order to further address a role of epigenetic modifications in DIDO3 localization, we made a mutant of the Dido gene that produces a truncated DIDO3 protein. This truncated protein, which lacks the histone-binding domain, is incorporated in the synaptonemal complex irrespective of histone trimethylation status. DIDO3 protein truncation in Dido mutant mice causes mild meiotic defects, visible as gaps in the synaptonemal complex, but allows for normal meiotic progression. Our results indicate that histone H3 lysine 4 demethylation modulates DIDO3 localization in meiosis and suggest epigenetic regulation of the synaptonemal complex.

No abstract

Academic papers, like genes, code for ideas or technological innovations that structure and transform the scientific organism and consequently the society at large. Genes are subject to the process of natural selection which ensures that only the fittest survive and contribute to the phenotype of the organism. The process of selection of academic papers, however, is far from natural. Commercial for-profit publishing houses have taken control over the evaluation and access to scientific information with serious consequences for the dissemination and advancement of knowledge. Academic authors and librarians are reacting by developing an alternative publishing system based on free-access journals and self-archiving in institutional repositories and global disciplinary libraries. Despite the emergence of such trends, the journal monopoly, rather than the scientific community, is still in control of selecting papers and setting academic standards. Here we propose a dynamical and transparent peer review process, which we believe will accelerate the transition to a fully open and free-for-all science that will allow the natural selection of the fittest ideas.

No abstract