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A NOVEL ROLE FOR THE FANCONI ANEMIA PATHWAY IN REPLICATION OF B(A)P-ADDUCTED DNA

Award Number: R01ES016280
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2008
PERIOD OF PERFORMANCE END DATE: 05/31/2013

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A NOVEL ROLE FOR THE FANCONI ANEMIA PATHWAY IN REPLICATION OF B(A)P-ADDUCTED DNA - DESCRIPTION (provided by applicant): The broad long-term objective of this proposal is to elucidate the role of the Fanconi Anemia (FA) pathway in protecting cells from the carcinogenic effects of Benzo[a]pyrene (B[a]P)-induced DNA damage. B[a]P is an abundant and ubiquitous environmental carcinogen that is metabolized intracellularly to generate Benzo[a]pyrene Di-hydrodiol-Epoxide (BPDE). BPDE-induced DNA damage triggers Rad18 (an E3 ligase)- dependent mono-ubiquitination of PCNA and recruitment of the specialized DNA polymerase Pol kappa to replication forks. In contrast with replicative DNA polymerases which stall at sites of DNA damage, Pol kappa can perform DNA synthesis using BPDE-adducted DNA as a template. Pol kappa-mediated TLS enables cells to tolerate the mutagenic and lethal effects of BPDE adducts, thereby contributing to genomic stability and tumor suppression. However, the molecular mechanism(s) of Pol kappa regulation are incompletely understood. Our preliminary studies suggest that the Fanconi Anemia (FA) proteins are intimately involved in Rad18 and Pol kappa- mediated TLS of B[a]P lesions. The Specific Aims of this proposal are: (1) To determine the molecular basis for BPDE-induced interaction between FANCD2 (the putative effector of the FA pathway) and Pol kappa. (2) To determine the mechanism by which Rad18 activates the FA pathway. (3) To test the interdependence of the FA and TLS pathways. Aim 1 will mutate ubiquitin binding motifs in Pol kappa and determine the effect of these mutations on FANCD2 association. Additionally, we will test the role of the Pol kappa- and FA pathway-interacting protein REV1 in mediating Pol kappa-FANCD2 interactions. Aim 2 will test whether Rad18 modifies FANCD2 directly or via regulation of upstream FA core complex components. Aim 3 will determine whether FANC- deficiency compromises TLS of BPDE lesions and conversely, whether defective TLS affects activation of the FA pathway by BPDE. Results of our studies will provide a novel paradigm for mechanisms by which the FA pathway is coordinated with TLS enzymes in response to environmental B[a]P (and possibly other genotoxins) to maintain genomic stability. Our studies might help identify individuals that are at high-risk for environmental B[a]P-induced disease. Moreover, our work could lead to novel drug targets for cancer therapy: Similar to B[a]P, many chemotherapies are genotoxic and activate checkpoint pathways. We have shown that Pol kappa- or Rad18-deficiency sensitizes cells to B[a]P-induced death. Potentially, small molecules that target FA components, Rad18, Pol kappa, or other TLS enzymes could sensitize cancer cells to killing by chemotherapeutic agents. PUBLIC HEALTH RELEVANCE: Benzo[a]pyrene (B[a]P) is an abundant environmental pollutant that damages DNA thereby causing permanent changes to the genetic code (termed 'mutations') that can result in cancer. Our results suggest that a group of cellular proteins termed the 'Fanconi Anemia' proteins (FANCs) play a role in preventing environmental B[a]P- induced mutations. The proposed experiments aim to understand the mechanisms by which FANCs help cells tolerate the effects of environmentally-induced DNA damage and protect against cancer.


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 = $293,736 )
2012	2012	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Environmental Health	000	5	5/11/2012	NON-COMPETING CONTINUATION	$293,736
														Subtotal = $293,736

Issue Date FY: 2011 ( Subtotal = $293,736 )
2011	2011	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Environmental Health	000	4	6/3/2011	NON-COMPETING CONTINUATION	$293,736
														Subtotal = $293,736

Issue Date FY: 2010 ( Subtotal = $296,703 )
2010	2010	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Environmental Health	000	3	5/27/2010	NON-COMPETING CONTINUATION	$296,703
														Subtotal = $296,703

Issue Date FY: 2009 ( Subtotal = $299,700 )
2009	2009	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Environmental Health	001	2	7/8/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$299,700
2009	2008	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	1	7/8/2009	NEW	$0
														Subtotal = $299,700

Issue Date FY: 2008 ( Subtotal = $329,063 )
2008	2008	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	1	7/23/2008	NEW	$329,063
														Subtotal = $329,063

Grand Total All Awards = $1,512,938

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A NOVEL ROLE FOR THE FANCONI ANEMIA PATHWAY IN REPLICATION OF B(A)P-ADDUCTED DNA

Award Number: R01ES016280

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2008

PERIOD OF PERFORMANCE END DATE: 05/31/2013

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