Final Activity Report Summary - TELOMERES AND ANEUPLOIDY (Telomere dysfunction and aneuploidy)
Today we can say that aging, the fact that we as a population are steadily growing older, is one of the major risk factors that contribute to many diseases, especially cancer. As the cells in replicative tissues passing through cell cycles they are forced to satisfy checkpoint controls. These checkpoint controls are under constant pressure to ensure genomic integrity of the cells. Failure in doing so has fatal consequences and leads to uncontrolled cell divisions resulting in pre-cancerous lesions and eventually to cancer. Cancer is an important and one of the most threatening diseases in the western world. About 1.5 million people are getting diagnosed with cancerous diseases per year in Europe. This affects mostly the elderly population. Early detection parameters and new therapeutic strategies will help fighting cancer at early stages.
The work under this proposal was addressing the role of a newly described complex of the structural maintenance of chromosome (SMC) proteins 5 and 6 that has been shown to be involved to ensure the integrity of transmission of repetitive sequences in the budding yeast model system in the onset of chromosomal instabilities in human cells. We were been able to dissect the functions of both proteins individually and found that even though both are involved in separate pathways, both ensure genomic integrity independently. We found that the lack of SMC5 in combination with another member of the complex, MMS21 a SUMO-ligase that modifies a variety of nuclear proteins and therefore determines their sub-cellular location and activity, leads to mitotic delay at the G2/M interphase. While under this condition the spindle organisation seems to be normal we found sister chromatids prematurely separated allowing them to partially clustering around spindle poles. This indicates a role for SMC5 and its partner MMS21 in the cohesion of sister chromatids.
The lack of SMC6 on the other hand did not perturb mitosis, even though an elevated number of cells with anaphase and consequently interphase chromosome bridges were observed. How much of these bridges are of proteinaceous nature needs to be still investigated especially since another hypothesis for generating chromosomal instabilities is based on telomere dysfunction involving Breakage fusion bridge cycles which involves chromosomal end-to-end fusions after uncapping of telomeres and nonhomologous end-joining processes (NHEJ) to ligate the naked telomere end to another chromosome. As a consequence the cell proceeds into mitosis with an anaphase bridge, which leads either to an abrogative cycle or subsequently to another chromosome breakage insult when cells proceed to separate dicentric chromosomes.
Taken together our work focused on that interplay of chromosomal maintenance and ploidy changes. The here gathered data contribute to the basic cancer research. Basic research in this field will contribute to understand the first cellular response to chromosomal instabilities and maybe the onset of many cancers. This will further help the innovation of new drugs for the treatment and even prevention of cancers.
The work under this proposal was addressing the role of a newly described complex of the structural maintenance of chromosome (SMC) proteins 5 and 6 that has been shown to be involved to ensure the integrity of transmission of repetitive sequences in the budding yeast model system in the onset of chromosomal instabilities in human cells. We were been able to dissect the functions of both proteins individually and found that even though both are involved in separate pathways, both ensure genomic integrity independently. We found that the lack of SMC5 in combination with another member of the complex, MMS21 a SUMO-ligase that modifies a variety of nuclear proteins and therefore determines their sub-cellular location and activity, leads to mitotic delay at the G2/M interphase. While under this condition the spindle organisation seems to be normal we found sister chromatids prematurely separated allowing them to partially clustering around spindle poles. This indicates a role for SMC5 and its partner MMS21 in the cohesion of sister chromatids.
The lack of SMC6 on the other hand did not perturb mitosis, even though an elevated number of cells with anaphase and consequently interphase chromosome bridges were observed. How much of these bridges are of proteinaceous nature needs to be still investigated especially since another hypothesis for generating chromosomal instabilities is based on telomere dysfunction involving Breakage fusion bridge cycles which involves chromosomal end-to-end fusions after uncapping of telomeres and nonhomologous end-joining processes (NHEJ) to ligate the naked telomere end to another chromosome. As a consequence the cell proceeds into mitosis with an anaphase bridge, which leads either to an abrogative cycle or subsequently to another chromosome breakage insult when cells proceed to separate dicentric chromosomes.
Taken together our work focused on that interplay of chromosomal maintenance and ploidy changes. The here gathered data contribute to the basic cancer research. Basic research in this field will contribute to understand the first cellular response to chromosomal instabilities and maybe the onset of many cancers. This will further help the innovation of new drugs for the treatment and even prevention of cancers.