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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056888-16
Application #
8500333
Study Section
Special Emphasis Panel (ZRG1-OBT-B (02))
Program Officer
Janes, Daniel E
Project Start
1998-01-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
16
Fiscal Year
2013
Total Cost
$511,847
Indirect Cost
$231,995
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Inagaki, Akiko; Roset, Ramon; Petrini, John H J (2016) Functions of the MRE11 complex in the development and maintenance of oocytes. Chromosoma 125:151-62
Balestrini, Alessia; Nicolas, Laura; Yang-Lott, Katherine et al. (2016) Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model. Mol Cancer Res 14:185-95
Asai, Takashi; Hatlen, Megan A; Lossos, Chen et al. (2016) Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms. Sci Rep 6:22760
Sarek, Grzegorz; Vannier, Jean-Baptiste; Panier, Stephanie et al. (2015) TRF2 recruits RTEL1 to telomeres in S phase to promote t-loop unwinding. Mol Cell 57:622-35
Hohl, Marcel; Kochańczyk, Tomasz; Tous, Cristina et al. (2015) Interdependence of the rad50 hook and globular domain functions. Mol Cell 57:479-91
Al-Ahmadie, Hikmat; Iyer, Gopa; Hohl, Marcel et al. (2014) Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy. Cancer Discov 4:1014-21
Roth, Susanne; Rottach, Andrea; Lotz-Havla, Amelie S et al. (2014) Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β 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
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
Gupta, Gaorav P; Vanness, Katelynd; Barlas, Afsar et al. (2013) The Mre11 complex suppresses oncogene-driven breast tumorigenesis and metastasis. Mol Cell 52:353-65

Showing the most recent 10 out of 51 publications