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DNA DAMAGE CHECKPOINT AND CANCER

Award Number: R01CA090631
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2001
PERIOD OF PERFORMANCE END DATE: 08/31/2011

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DNA DAMAGE CHECKPOINT AND CANCER - DESCRIPTION (provided by applicant): The long time goals of this project are to understand, in molecular terms, how signaling networks regulate the cellular response to DNA damage. Cellular DNA must be accurately replicated and transmitted to each daughter cell during cell division. In response to various forms of genotoxic stress, cells activate complex protein kinase signaling pathways, such as ATM, to arrest the cell cycle, recruit DNA repair machinery, and re-enter the cell cycle once the damage is resolved, or if the damage is overwhelming, induce apoptosis or cell senescence. In the present proposal, we explore the function of BAAT1, an activator of ATM under conditions of cell stress, as a critical regulator of DNA damage-sensing pathway in response to environmental and endogenous types of DNA damage. We use a combination of extensive biochemistry and molecular cell biology to explore the signal transduction mechanisms involved in BAAT1/ATM activation after DNA damage induced by ionizing radiation (IR) and chemicals, and examine how BAAT1/ATM pathway functions together with other checkpoint proteins such as NBS1, to control cell cycle progression after genotoxic stress in cells in culture. We go on to develop a conditional BAAT1 knockout mouse to explore whether BAAT1 functions in tumor suppressor pathway in genetically defined models of breast cancer, and in environmental carcinogen-induced models of colorectal cancer. Finally, we explore whether down-regulation of BAAT1 facilitates cell death after intentional chemically-induced DNA damage such as chemotherapy. These studies should clarify how signals from ATM pathway, a global stress- responsive network that is activated by a wide variety of toxic insults, integrate with those from dedicated DNA damage response pathways, to regulate the cellular response to genotoxic stress. The results of the proposed experiments should reveal whether BAAT1 functions as a tumor suppressor gene that modulates the risk of cancer after exposure to environmental agents, and whether specific targeting of BAAT1/ATM would be of therapeutic value for sensitizing tumors to the cytotoxic effects of conventional chemotherapy. PUBLIC HEALTH RELEVANCE: The long time goals of this project are to understand, in molecular terms, how signaling networks regulate the cellular response to DNA damage. Cellular DNA must be accurately replicated and transmitted to each daughter cell during cell division. In response to various forms of genotoxic stress, cells activate complex protein kinase signaling pathways to arrest the cell cycle, recruit DNA repair machinery, and re-enter the cell cycle once the damage is resolved, or if the damage is overwhelming, induce apoptosis or cell senescence. DNA lesions arise as a consequence of both endogenous cellular processes such as metabolic reactions and DNA replication, and through exposure of cells to environmental mutagens including chemical carcinogens, UV light and gamma-radiation. A variety of incompletely understood genetic factors increase the risk for, and consequences of, DNA damage, and cell cycle control. Two canonical protein kinase pathways are responsible for arresting the cell cycle in response to damaged DNA - the ATR-Chk1 pathway and the ATM-Chk2 pathway. Disruption of either pathway is associated with increased sensitivity of cells to various DNA damaging agents, as well as with increase risk of various human cancers. We recently identified a protein, termed BAAT1 (BRCA1 Associated protein required for ATM activation-1). Biochemical studies have demonstrated that BAAT1 is required for autophosphorylation of ATM Ser1981, which has been shown to be essential for the activation of ATM under conditions of genotoxic stresses. Importantly, it has been revealed that the ATM pathway is a much more global stress-sensing pathway, and can be activated by different types of cellular stress including gamma-radiation, NaCl, chloroquine and Trichostatin A. We therefore hypothesize that the proper cellular response to genotoxic stress must involve the functional integration of dedicated DNA damage response pathways with stress kinase signaling pathways. In this proposal we seek to clarify how the BAAT1-ATM pathway is activated in response to DNA damage, how the BAAT1-ATM pathway is functionally interconnected with other DNA damage-sensing proteins, and whether cell specific-disruption of the BAAT1 pathway using RNA gene targeting approaches facilitates tumor development by genetic and environmental lesions or alters the response to tumors to DNA damaging chemotherapy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2012 ( Subtotal = -$228,750 )
2012	2011	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Cancer Cause and Prevention Research	000	9	2/15/2012	NON-COMPETING CONTINUATION	-$228,750
														Subtotal = -$228,750

Issue Date FY: 2011 ( Subtotal = $305,540 )
2011	2011	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Cancer Cause and Prevention Research	000	9	5/18/2011	NON-COMPETING CONTINUATION	$305,540
														Subtotal = $305,540

Issue Date FY: 2010 ( Subtotal = $314,989 )
2010	2010	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Cancer Cause and Prevention Research	000	8	5/24/2010	NON-COMPETING CONTINUATION	$314,989
														Subtotal = $314,989

Issue Date FY: 2009 ( Subtotal = $314,989 )
2009	2009	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Cancer Cause and Prevention Research	000	7	4/27/2009	NON-COMPETING CONTINUATION	$314,989
														Subtotal = $314,989

Issue Date FY: 2008 ( Subtotal = $314,989 )
2008	2008	EVANSTON NORTHWESTERN HEALTHCARE RESEARCH INSTITUTE	2650 RIDGE AVENUE	EVANSTON	IL	60201	COOK	USA	Cancer Cause and Prevention Research	000	6	8/7/2008	COMPETING CONTINUATION	$314,989
														Subtotal = $314,989

Issue Date FY: 2006 ( Subtotal = $297,227 )
2006	2006	EVANSTON NORTHWESTERN HEALTHCARE RESEARCH INSTITUTE	2650 RIDGE AVENUE	EVANSTON	IL	60201	COOK	USA	Cancer Biology Research	000	5	8/17/2006	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$297,227
														Subtotal = $297,227

Issue Date FY: 2005 ( Subtotal = $339,424 )
2005	2005	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Cancer Biology Research	000	4	8/2/2005	NON-COMPETING CONTINUATION	$339,424
														Subtotal = $339,424

Issue Date FY: 2004 ( Subtotal = $339,424 )
2004	2004	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Cancer Biology Research	000	3	8/31/2004	NON-COMPETING CONTINUATION	$339,424
														Subtotal = $339,424

Issue Date FY: 2003 ( Subtotal = $339,424 )
2003	2003	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Cancer Biology Research	000	2	6/30/2003	NON-COMPETING CONTINUATION	$339,424
														Subtotal = $339,424

Issue Date FY: 2002 ( Subtotal = $339,424 )
2002	2002	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Cancer Biology Research	000	1	6/10/2002	NEW	$339,424
														Subtotal = $339,424

Grand Total All Awards = $2,676,680

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DNA DAMAGE CHECKPOINT AND CANCER

Award Number: R01CA090631

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2001

PERIOD OF PERFORMANCE END DATE: 08/31/2011

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