Tour-de-Force

Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007General Introduction: A Tour always has a StartThis research proposal is aimed at linking two of the most important cellular processes: cell cycleprogression and mitochondrial activity. Firstly, an introduction into the topic will be provided as to explainthese crucial process after which the relevance of linking the two will be put forward. The four projectswithin this program all explore different aspects of the link between the cell cycle and mitochondria. Withinthis introduction the essence of the four projects is provided.The Cell Cycle and the MitochondriaSelf-reproduction is perhaps the most fundamental characteristic of life. Self-reproduction in cellsis accomplished through growth and division into separate daughter cells. The division of cells must be aclosely regulated mechanism to ensure equality among progeny cells, and it is regulated by controlledprogression through the cell cycle (figure 1). In general, the cell cycle can be said to consist of four phases.In S-phase, the DNA replicates so that in cell division both daughter cells will receive the same, complete,genomic information. In M-phase (mitosis) the actual division takes place, involving first nuclear divisionand then the actual cell division. In between, there are two resting phases, named G1 and G2, in whichcell growth takes place. Cells can pause in the G1 phase by going into the G0 phase, which means thatthey stop progressing through the cell cycle. This cell cycle arrest can be reversible (quiescence) orirreversible (senescence), as is the case in certain differentiated cell types. Additionally, variouscheckpoints, that control progression from one phase to another, ensure that various standards have beenreached before continuation is wished for.Figure 1 The different phases of thecell cycle.Source: Mitosis: Mitosis and the Cell DivisionCycle;http://www.phschool.com/science/biology_place/biocoach/mitosisisg/cellcyc.htmlThe abovementioned checkpoints ensure optimal conditions for cell cycle progression. The firstcheckpoint in animal cells that one encounters during an imaginary tour through the cell cycle is therestriction point. This checkpoint controls G1 to S succession, through the evaluation of growth factoravailability, DNA damage and energy levels. By continuation of the imaginary tour, one will pass by thecheckpoints in the middle of S phase and in the end of G2 phase, which mainly function to evaluate DNAdamage. In addition, the G2 checkpoint ensures that mitosis is only realized after full replication of theDNA. Lastly, the spindle assembly checkpoint in late M phase monitors the alignment of chromosomes onthe mitotic spindle, such that distribution will be equal over progeny cells.Transition through the various checkpoints discussed above is influenced by many differentfactors, the most important ones being the Cyclins and the Cyclin-dependant kinases, which directly allowphase arrest or succession. Different Cyclins interact with more or less Cyclin-specific Cdk’s, althoughthere is evidence for partial redundancy. Different Cyclin-Cdk complexes are associated with differentphases of the cell cycle. Cyclins and Cdk’s, and moreover the formation of their complexes, is notfunctional by itself, but rather influenced through various pathways. Therefore, the cell cycle might beregulated by various intrinsic and extrinsic factors.SCI 332 Advanced Molecular Cell Biology Research Proposal 5