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Synthetic lethality and synthetic cytotoxicity strategies for selective killing of ATM deficient cells Li, Xuesong


Chromosome instability (CIN) is a hallmark of cancer cells and could, in theory, be exploited in the design of cancer therapeutics. Tumor cells harboring CIN mutations may be dependent on certain DNA repair pathways for viability. Thus, inhibition of specific DNA repair enzymes may enhance the CIN phenotype to an intolerable level, or may sensitize cells to DNA damage stress. To test this hypothesis, I focused on the CIN gene ATM, which is often mutated in human tumors. I hypothesized that knockdown of certain second site DNA repair genes would selectively kill ATM-deficient cells resulting in synthetic lethality (SL), or sensitize ATM-deficient cells to a sub-lethal dose of DNA damaging agent resulting in synthetic cytotoxicity (SC). The goal of this research is to use budding yeast as a model system to identify candidate SL or SC interaction partner genes for ATM with/without sub-lethal doses of DNA damaging agents, using mutations in the yeast ATM homologues, TEL1 and MEC1. I tested for interactions with TEL1 and MEC1 in a small matrix of three DNA repair genes (RAD27, TDP1 and TPP1) and four DNA damaging agents (hydroxyurea, 5-fluorouracil, bleomycin, and camptothecin). I also performed a genome-wide screen for interactions between TEL1 and ~5000 non-essential genes, both in the presence and absence of low doses of camptothecin. I discovered one SL interaction with MEC1 and fourteen SC interactions with TEL1. Most of the SC interaction partner genes are involved in DNA repair and show sensitivity specifically to camptothecin. These data provide a rationale for testing specific combination therapies for selective killing of cancer cells bearing ATM mutations. Specifically, the Shu complex, Ku complex, Rrm3, Rad27 and CK2β subunits can be further tested as potential combination therapeutic targets, together with a sub-lethal dose of camptothecin, to kill ATM-deficient cancer cells.

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