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A Tale of Two Projects: Basis for Centrosome Amplification after DNA Damage and Practical Assessment of Photodamage in Live-Cell Imaging: A Dissertation

This thesis comprises two separate studies that focus on the consequences of cellular damage. The first investigates the effects of DNA damage on centriole behavior and the second characterizes phototoxicity during live-cell imaging. Cancer treatments such as ionizing radiation and/or chemotherapeutic DNA damaging agents are intended to kill tumor cells, but they also damage normal proliferating cells. Although centrosome amplification after DNA damage is a well-established phenomenon for transformed cells, it is not fully understood in untransformed cells. The presence of extra centrosomes in normal cell populations raises the chances of genomic instability, thus posing additional threats to patients undergoing these therapies. I characterized centriole behavior after DNA damage in synchronized untransformed (RPE1) human cells. Treatment with the radiomimetic drug, Doxorubicin, prolongs G2 phase by at least 72hrs, where 52% of cells display disengaged centrioles and 10% contain extra centrioles. This disengagement is mediated by Plk and APC/C activities both singly and in combination. Disengaged centrioles are associated with maturation markers suggesting they are capable of organizing spindle poles. Despite the high incidence of centriole disengagement, only a small percentage of centrioles reduplicate due to p53/p21 dependent inhibition of Cdk2 activity. Although all cells become prolonged in G2 phase, 14% eventually go through mitosis, of which 26% contain disengaged or extra centrioles.