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. We have established that extreme cancer predisposition results from mutant combinations of RadSOS allele in the mouse, and determined the target cell of this pathology to be the hematopoietic stem cell. Further supporting the Mre11 complex's critical role in the suppression of malignancy is the fact that two distinct human chromosome instability syndromes associated with cancer predisposition are caused by mutations affecting the complex. Understanding its mechanism of tumor suppression is thus a high priority. 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 address the cancer preventing functions of the complex in three primary foci. First we have established reagents and experimental strategies to define the structural role of the Mre11 complex in recombinational DNA repair in three contexts: during normal proliferation, in response to clastogens in vegetatively growing cells, and in meiotic recombination. Second, we will address the idea that the nuclease function of the Mre11 complex, and its contribution to the resolution of covalent protein-DNA complexes influences the suppression of malignancy by these highly conserved proteins. Third, the role of the Mre11 complex in post-mitotic cells will be examined.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056888-13
Application #
7858544
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Hagan, Ann A
Project Start
1998-01-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
13
Fiscal Year
2010
Total Cost
$537,902
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Park, Young Bong; Hohl, Marcel; Padjasek, Micha? et al. (2017) Eukaryotic Rad50 functions as a rod-shaped dimer. Nat Struct Mol Biol 24:248-257
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
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
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
Hohl, Marcel; Kocha?czyk, Tomasz; Tous, Cristina et al. (2015) Interdependence of the rad50 hook and globular domain functions. Mol Cell 57:479-91
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
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
Roset, Ramon; Inagaki, Akiko; Hohl, Marcel et al. (2014) The Rad50 hook domain regulates DNA damage signaling and tumorigenesis. Genes Dev 28:451-62
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
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

Showing the most recent 10 out of 54 publications