Functional and genetic interactions of Mus81 with the Chk2-p53 tumor suppressor pathway

The progression of a normal cell to a cancer cell is thought to involve the acquisition of several mutations that result in unregulated proliferation, improper differentiation, and increased survival phenotypes. Much of classical cancer research has focused on searching for novel genes that contribute to either tumor suppression or oncogenesis. However, since multiple mutational hits are required to drive cancer, studying the interaction and cooperation of genes in cancer progression and suppression may provide models that more accurately depict human carcinogenesis and provide new therapeutical insights.;In yeast and mammalian cells, the Mus8l endonuclease plays a role in DNA repair and recombination by cleaving branched DNA substrates such as replication forks, 3'DNA flaps, and Holliday Junctions. To study the in vivo functions of mammalian Mus81, our lab generated Mus81 -/- mice, Mus81-/- mice are viable and fertile but are extremely sensitive to the interstrand crosslinking agent MMC. Significantly, Mus81+/- and Mus81-/- cells display spontaneous chromosomal damage and Mus81+/- and Mus81 -/- mice are susceptible to spontaneous tumorigenesis. These findings have identified Mus8l as an important caretaker of the genome and established it as a candidate haploinsufficient tumor suppressor. The focus of this thesis is the investigation of the genetic interplay between Mus81 and the Chk2-p53 tumor suppressor pathway in DNA repair responses and tumor suppression.;This thesis demonstrates that p53 plays a critical role in eliminating damaged Mus81-/- cells. Furthermore, our findings demonstrate that dual inactivation of Mus81 and p53 results in a synergistic increase in genomic instability, accelerated tumorigenesis, and a profound predisposition for sarcoma development. Thus, Mus81 inactivation may play a critical role in human sarcoma development.;Contrastingly, we found that Chk2 does not participate in eliminating DNA damaged Mus81-/- cells. Furthermore, loss of Chk2 results in a rescue of the genomic instability inherent in Mus81-/- mice and remarkably rescues the tumor susceptibility of Mus81-/- mice. Thus, our study suggests that in response to DNA damage in Mus81-/- cells, Chk2 does not mimic p53 as a gatekeeper and tumor suppressor, but instead promotes oncogenesis.