Abstract

In this proposal, we will continue to exploit the mouse strains established in the first funding period to address the mechanisms of the Mre11 complex's actions in chromosome metabolism. In addition, we will test the hypothesis that proteins interacting with the Nbs1 N terminus are critical for regulation of DNA damage responses. We expect that these approaches will continue to provide important insights regarding the role of the Mre11 complex in the maintenance of genomic integrity and the suppression of malignancy. The governing hypothesis of this proposal is that, from its association with chromatin, the Mre11 complex functions as a hub of the DNA damage response. We propose that this association is a prerequisite for its influence on sister chromatid interaction during DSB repair and DNA damage signaling. In addition, we propose that its signaling function takes place via protein interactions that include those governed by the N terminus of Nbs1. We will test these hypotheses through a combination of biochemical and genetic approaches in human cells and mice.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM059413-06
Application #
6732300
Study Section
Radiation Study Section (RAD)
Program Officer
Wolfe, Paul B
Project Start
1999-05-01
Project End
2007-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
6
Fiscal Year
2004
Total Cost
$465,376
Indirect Cost

  Institution

Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Hung, Putzer J; Johnson, Britney; Chen, Bo-Ruei et al. (2018) MRI Is a DNA Damage Response Adaptor during Classical Non-homologous End Joining. Mol Cell 71:332-342.e8
Henssen, Anton G; Reed, Casie; Jiang, Eileen et al. (2017) Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors. Sci Transl Med 9:
Kim, Jun Hyun; Grosbart, Malgorzata; Anand, Roopesh et al. (2017) The Mre11-Nbs1 Interface Is Essential for Viability and Tumor Suppression. Cell Rep 18:496-507
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
Rocha, Pedro P; Raviram, Ramya; Fu, Yi et al. (2016) A Damage-Independent Role for 53BP1 that Impacts Break Order and Igh Architecture during Class Switch Recombination. Cell Rep 16:48-55
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
Katyal, Sachin; Lee, Youngsoo; Nitiss, Karin C et al. (2014) Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes. Nat Neurosci 17:813-21
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
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
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

Showing the most recent 10 out of 46 publications