The MRN-ATM pathway is primarily involved in sensing, signaling, and repairing DNA double-strand breaks (DSBs). DSBs arise as a consequence of external insults, such as ionizing radiation and are generated in all cycling cells during DNA replication. If unrepaired, they may lead to mutations and chromosome rearrangements, translocations or loss. The long-term objective of this proposal is to understand how the MRN-ATM pathway regulates DNA damage response to DSBs. Specifically, we will study how ATM and MRN interact with DNA, how ATM modulates MRN-DNA interactions and conversely how MRN affects ATM's behavior on DNA. Next, we will investigate the role of damaged DNA in ATM activation. Finally, we will determine how MRN and ATM cooperate to maintain genome stability in the presence of DSBs. Our system to analyze these questions remains Xenopus egg cell free extracts. The MRN-ATM pathway is a central node in the response to DSBs and defects in this pathway or its downstream targets are associated with inherited cancer susceptibility syndromes including Ataxia-Telangiectasia (A-T), Ataxia Telangiectasia like disorder (ATLD), Nijmegen Breakage Syndrome (NBS), Fanconi Anemia (FA), BRCA1-associated breast and ovarian cancer susceptibility. We anticipate that our studies will help explain how maintenance of genome stability by the MRN-ATM pathway protects from tumorigenesis. Furthermore, since the MRN-ATM pathway is a target for therapeutic intervention, a better mechanistic understanding of how the MRN-ATM pathway functions could help to identity compounds with radio-protective or radio-sensitizing potential.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092245-10
Application #
8081784
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2001-07-01
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
10
Fiscal Year
2011
Total Cost
$276,879
Indirect Cost
Name
Columbia University (N.Y.)
Department
Genetics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Aparicio, Tomas; Baer, Richard; Gottesman, Max et al. (2016) MRN, CtIP, and BRCA1 mediate repair of topoisomerase II-DNA adducts. J Cell Biol 212:399-408
Sato, Mai; Rodriguez-Barrueco, Ruth; Yu, Jiyang et al. (2015) MYC is a critical target of FBXW7. Oncotarget 6:3292-305
Aparicio, Tomas; Baer, Richard; Gautier, Jean (2014) DNA double-strand break repair pathway choice and cancer. DNA Repair (Amst) 19:169-75
Rozier, Lorene; Guo, Yige; Peterson, Shaun et al. (2013) The MRN-CtIP pathway is required for metaphase chromosome alignment. Mol Cell 49:1097-107
Williams, Hannah L; Gottesman, Max E; Gautier, Jean (2013) The differences between ICL repair during and outside of S phase. Trends Biochem Sci 38:386-93
Srinivasan, Seetha V; Dominguez-Sola, David; Wang, Lily C et al. (2013) Cdc45 is a critical effector of myc-dependent DNA replication stress. Cell Rep 3:1629-39
Peterson, Shaun E; Li, Yinyin; Wu-Baer, Foon et al. (2013) Activation of DSB processing requires phosphorylation of CtIP by ATR. Mol Cell 49:657-67
Williams, Hannah L; Gottesman, Max E; Gautier, Jean (2012) Replication-independent repair of DNA interstrand crosslinks. Mol Cell 47:140-7
Peterson, Shaun E; Li, Yinyin; Chait, Brian T et al. (2011) Cdk1 uncouples CtIP-dependent resection and Rad51 filament formation during M-phase double-strand break repair. J Cell Biol 194:705-20
Srinivasan, Seetha V; Gautier, Jean (2011) Study of cell cycle checkpoints using Xenopus cell-free extracts. Methods Mol Biol 782:119-58

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