This proposal addresses the mechanistic and genetic basis for the Mre11 complex's role in the suppression of malignancy. Using yeast and mouse models, it focuses primarily on DNA repair and DNA damage signaling alterations imparted by alleles of RAD50 that affect the coiled-coil and hook domains of the protein. We the mutants derived in this effort are separations of function that will allow us to define the role of particular Mre11 complex-dependent mechanisms meiosis, DNA repair, and the suppression of tumorigenesis. The governing hypothesis of this proposal is that the Mre11 complex suppresses tumorigenesis through its affect on chromosome integrity in addition to its influence on DNA damage signaling. We propose a series of experiments in mice and yeast to address the cancer preventing functions of the complex. First, we investigate the importance of recruitment of DNA repair factors by the Mre11 complex. Second, we examine the effect of mutations within the Rad50 hook domain on NHEJ and HR. Third, we integrate the knowledge gained in the first two Aims for the analysis of new mouse models for Rad50 dysfunction that selectively impair NHEJ. Genetic interactions with these mice and mice mutants in p53, ATM and PTEN will be examined to test the hypothesis that chromosome instability in Rad50 mutants will increase the penetrance of mutations affecting these tumor suppressor proteins and predispose to cancer.
Genome instability is a hallmark of cancer, and defects in the DNA damage response, which is required for the maintenance of genome stability are associated with cancer as well as human syndromes associated with reproductive, developmental and neurological defects. We address the functions of a central DNA damage response component, the Mre11 complex. This complex has been implicated in human chromosome instability syndromes associated with increase risk of malignancy, and has also found to be defective in sporadic cancers. The experiments described in this application examine the Mre11 complex and have the potential to provide insights regarding the mechanisms underlying cancer predisposition, as well as those that may present suitable targets for interdiction in therapeutic settings.
|Roth, Susanne; Rottach, Andrea; Lotz-Havla, Amelie S et al. (2014) Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1? production. Nat Immunol 15:538-45|
|Roset, Ramon; Inagaki, Akiko; Hohl, Marcel et al. (2014) The Rad50 hook domain regulates DNA damage signaling and tumorigenesis. Genes Dev 28:451-62|
|Balestrini, Alessia; Ristic, Dejan; Dionne, Isabelle et al. (2013) The Ku heterodimer and the metabolism of single-ended DNA double-strand breaks. Cell Rep 3:2033-45|
|Ballew, Bari J; Joseph, Vijai; De, Saurav et al. (2013) A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. PLoS Genet 9:e1003695|
|Hohl, Marcel; Kwon, Youngho; Galvan, Sandra Munoz et al. (2011) The Rad50 coiled-coil domain is indispensable for Mre11 complex functions. Nat Struct Mol Biol 18:1124-31|
|Stracker, Travis H; Williams, Bret R; Deriano, Ludovic et al. (2009) Artemis and nonhomologous end joining-independent influence of DNA-dependent protein kinase catalytic subunit on chromosome stability. Mol Cell Biol 29:503-14|
|Halberg, Richard B; Waggoner, Jesse; Rasmussen, Kristen et al. (2009) Long-lived Min mice develop advanced intestinal cancers through a genetically conservative pathway. Cancer Res 69:5768-75|
|Stracker, Travis H; Usui, Takehiko; Petrini, John H J (2009) Taking the time to make important decisions: The checkpoint effector kinases Chk1 and Chk2 and the DNA damage response. DNA Repair (Amst) :|
|Adelman, Carrie A; De, Saurav; Petrini, John H J (2009) Rad50 is dispensable for the maintenance and viability of postmitotic tissues. Mol Cell Biol 29:483-92|
|Usui, Takehiko; Foster, Steven S; Petrini, John H J (2009) Maintenance of the DNA-damage checkpoint requires DNA-damage-induced mediator protein oligomerization. Mol Cell 33:147-59|
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