Heterogeneity, turn-over rate and karyotype space shape susceptibility to missegregation-induced extinction

The incidence of somatic copy number alterations (SCNAs) per base pair of the genome is orders of magnitudes larger than that of point mutations. This makes SCNAs phenotypically effective. One mitotic event stands out in its potential to significantly change a cell's SCNA burden -- a chromosome missegregation. We have presented a general deterministic framework for modeling whole chromosome missegregations and use it to evaluate the possibility of missegregation-induced population extinction (MIE). The model predicts critical curves that separate viable from non-viable populations as a function of their turnover- and mis-segregation rates. Missegregation- and turnover rates estimated for nine cancer types are then compared to these predictions for various biological assumptions. The assumption of heterogeneous missegregation rates within a tumor was sufficient to explain the observed data. By contrast, when assuming constant mis-segregation rates, several cancers were located in regions predicted as unviable. Intra-tumor heterogeneity, including heterogeneity in mis-segregation rates, increases as tumors progress. Our predictions suggest that this intra-tumor heterogeneity hinders the chance of success of therapies aimed at MIE.

Plo1 Kinase Recruitment to the Spindle Pole Body and Its Role in Cell Division inSchizosaccharomyces pombe

Polo kinases execute multiple roles during cell division. The fission yeast polo related kinase Plo1 is required to assemble the mitotic spindle, the prophase actin ring that predicts the site for cytokinesis and for septation after the completion of mitosis ( Ohkuraet al., 1995 ; Bahler et al., 1998 ). We show that Plo1 associates with the mitotic but not interphase spindle pole body (SPB). SPB association of Plo1 is the earliest fission yeast mitotic event recorded to date. SPB association is strong from mitotic commitment to early anaphase B, after which the Plo1 signal becomes very weak and finally disappears upon spindle breakdown. SPB association of Plo1 requires mitosis-promoting factor (MPF) activity, whereas its disassociation requires the activity of the anaphase-promoting complex. The stf1.1 mutation bypasses the usual requirement for the MPF activator Cdc25 ( Hudson et al., 1990 ). Significantly, Plo1 associates inappropriately with the interphase SPB of stf1.1 cells. These data are consistent with the emerging theme from many systems that polo kinases participate in the regulation of MPF to determine the timing of commitment to mitosis and may indicate that pole association is a key aspect of Plo1 function. Plo1 does not associate with the SPB when septation is inappropriately driven by deregulation of the Spg1 pathway and remains SPB associated if septation occurs in the presence of a spindle. Thus, neither Plo1 recruitment to nor its departure from the SPB are required for septation; however, overexpression ofplo1+activates the Spg1 pathway and causes transient Cdc7 recruitment to the SPB and multiple rounds of septation.

DBF2 Protein Kinase Binds to and Acts through the Cell Cycle-Regulated MOB1 Protein

ABSTRACT The DBF2 gene of the budding yeast Saccharomyces cerevisiae encodes a cell cycle-regulated protein kinase that plays an important role in the telophase/G1 transition. As a component of the multisubunit CCR4 transcriptional complex, DBF2 is also involved in the regulation of gene expression. We have found that MOB1, an essential protein required for a late mitotic event in the cell cycle, genetically and physically interacts with DBF2. DBF2 binds MOB1 in vivo and can bind it in vitro in the absence of other yeast proteins. We found that the expression of MOB1 is also cell cycle regulated, its expression peaking slightly before that of DBF2 at the G2/M boundary. While overexpression of DBF2 suppressed phenotypes associated withmob1 temperature-sensitive alleles, it could not suppress amob1 deletion. In contrast, overexpression of MOB1 suppressed phenotypes associated with adbf2-deleted strain and suppressed the lethality associated with a dbf2 dbf20 double deletion. A mob1temperature-sensitive allele with a dbf2 disruption was also found to be synthetically lethal. These results are consistent with DBF2 acting through MOB1 and aiding in its function. Moreover, the ability of temperature-sensitive mutated versions of the MOB1 protein to interact with DBF2 was severely reduced, confirming that binding of DBF2 to MOB1 is required for a late mitotic event. While MOB1 and DBF2 were found to be capable of physically associating in a complex that did not include CCR4, MOB1 did interact with other components of the CCR4 transcriptional complex. We discuss models concerning the role of DBF2 and MOB1 in controlling the telophase/G1 transition.

Experimental Obliteration of the Preprophase Band Alters the Site of Cell Division, Cell Plate Orientation and Phragmoplast Expansion in Adiantum Protonemata

Division sites in higher plant cells are known to be determined before mitosis, and cell plates are precisely inserted into the predetermined division sites at the end of cytokinesis by unknown mechanisms. When apically growing protonemal cells of the fern, Adiantum capillus-veneris L., grown under red light are transferred to the dark, apical growth ceases and the protonemal cells then divide. However, this mitotic event can be influenced by subsequent exposure to light. If red-light pre-cultured protonemata are incubated in the dark and then transferred back to red light (after 28–36 h), apical growth resumes and the nuclei migrate toward the growing tips; interestingly, mitosis still occurs, although in an altered fashion. In the re-irradiated cells, timing of the premitotic nuclear positioning is delayed markedly and irregularly oriented cell plates are frequently observed. Re-irradiation with red light also causes an increase in cells without preprophase bands (PPBs) at prophase and the irregular expansion of the phragmoplast at late telophase, while early phragmoplast microtubule (MT) organization takes place normally. These data suggest the indirect involvement of PPBs in the guidance of phragmoplast expansion.

‘Exceptional sons’ from Drosophila melanogaster mothers carrying a balancer X chromosome

SummaryThis study reports on exceptional males which are obtained by using Drosophila melanogaster mothers carrying the balancers In(l)FM6 or In(l)FM7 as one of their X chromosomes. The phenomenon was first observed in interspecific crosses between D. melanogaster females and males of its closest relatives which normally produce unisexual female hybrid progeny. Whereas hybrid sons from these crosses die as third instar larvae, the presence of the particular X balancers in the mother allows a low percentage of sons to survive. Similar sterile males are also observed among non- hybrid flies. Data are presented which suggest that the males thus generated could be hyperploid for part of their X chromosome as a result of a meiotic event in their mothers or else they could start life as female zygotes and change sex through a mitotic event at an early stage.