We will investigate the controls for centriole duplication and how prolonged prometaphase blocks daughter cell proliferation. Since mitotic fidelity depends upon the cell containing just two centrosomes, centrosome duplication must be under tight numerical and temporal control. Extra centrosomes (centrosome amplification) at mitosis can lead to unequal chromosome distribution and consequent genomic instability which is a driving force in multi- step carcinogenesis.
In Aim 1 we test a model that can explain centrosome amplification after DNA damage, a well established but poorly understood phenomenon. Radiation and radiomimetic drugs are currently used to treat human tumors. Follow up radiation therapy can cause DNA damage in proliferating normal cells in the tumor region - particularly after surgery.
In Aim 2 we will investigate if and how geminin plays a role in enforcing the block to centrosome reduplication during S and G2 phases of the cell cycle. The centrosome intrinsic block to reduplication is of critical importance in preventing centrosome amplification.
In Aim 3 we test if targeting of Cdk2-cyclin E to the centrosome is required for centrosome duplication or if soluble pools of this kinase complex are sufficient to drive centrosome duplication. This explores the importance of local control of centrosome duplication and provides insight into how zygotes control centrosome duplication despite constitutively high cytoplasmic Cdk2-cyclin E activity.
In Aim 4 we will further characterize the basis for our discovery that prolonged prometaphase causes an irreversible block to daughter cell proliferation despite the normal division of the mother cell. This proliferation block can serve to handle mitotic defects due to environmental toxins that are never resolved but allow satisfaction of the mitotic checkpoint and consequent improper completion of mitosis. We will also explore the possibility that chemotherapeutic regimes using microtubule targeting drugs could lead to stem cells withdrawing from the cell cycle thereby compromising tissue regeneration, wound healing, and tissue maintenance.
The research outlined in this proposal investigates the mechanisms used by the cell to prevent errors in cell division which compromise genomic integrity. Genomic instability, a hallmark of many human cancers, is a recognized driving force in the evolution of aggressive growth characteristics and resistance to chemotherapeutic agents in clinical use.
|Sluder, Greenfield (2014) One to only two: a short history of the centrosome and its duplication. Philos Trans R Soc Lond B Biol Sci 369:|
|Douthwright, Stephen; Sluder, Greenfield (2014) Link between DNA damage and centriole disengagement/reduplication in untransformed human cells. J Cell Physiol 229:1427-36|
|Nordberg, Joshua J; Sluder, Greenfield (2013) Practical aspects of adjusting digital cameras. Methods Cell Biol 114:151-62|
|Krzywicka-Racka, Anna; Sluder, Greenfield (2011) Repeated cleavage failure does not establish centrosome amplification in untransformed human cells. J Cell Biol 194:199-207|
|Uetake, Yumi; Sluder, Greenfield (2010) Prolonged prometaphase blocks daughter cell proliferation despite normal completion of mitosis. Curr Biol 20:1666-71|
|Sluder, Greenfield; Khodjakov, Alexey (2010) Centriole duplication: analogue control in a digital age. Cell Biol Int 34:1239-45|
|Varmark, Hanne; Sparks, Cynthia A; Nordberg, Joshua J et al. (2009) DNA damage-induced cell death is enhanced by progression through mitosis. Cell Cycle 8:2951-63|
|Schnackenberg, Bradley J; Marzluff, William F; Sluder, Greenfield (2008) Cyclin E in centrosome duplication and reduplication in sea urchin zygotes. J Cell Physiol 217:626-31|
|Matijasevic, Zdenka; Krzywicka-Racka, Anna; Sluder, Greenfield et al. (2008) MdmX regulates transformation and chromosomal stability in p53-deficient cells. Cell Cycle 7:2967-73|
|Uetake, Yumi; Sluder, Greenfield (2007) Cell-cycle progression without an intact microtuble cytoskeleton. Curr Biol 17:2081-6|
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