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The role of DNA Polymerase Delta 4 in Lung Carcinogenesis Induced by Genotoxic Carcinogens

Award Number: R21ES036369
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: 06/18/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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The role of DNA Polymerase Delta 4 in Lung Carcinogenesis Induced by Genotoxic Carcinogens - ABSTRACT Lung cancer is the leading cause of cancer-related death in the world. Exposures to airborne carcinogens contribute significantly to lung carcinogenesis. Genotoxic carcinogens, which can come from environmental and/or occupational settings, are the most important causes of lung malignancy in humans. These include hexavalent chromium (Cr(VI)), nicotine-derived nitrosamine ketone (NNK), benzo(a)pyrene (BaP), and urethane. Exposure to these carcinogens can lead to formation of DNA adducts that induce DNA double-strand breaks. DNA damage is a key early event and the driving force of genetic abnormalities that lead to malignant transformation of normal lung epithelial cells. In humans, there are two forms of Polδ: Polδ4 and Polδ3. Polδ4 is a tetramer containing the p12 subunit which is absent in yeast. The degradation of p12 in response to DNA damage leads to the conversion of Polδ4 to Polδ3. This is a novel cellular regulatory system that orchestrates the formation of Polδ3 which plays a key role in DNA repair and replication. Our recent work shows that Polδ4 is the enzyme form that is involved in the key step in homology directed repair (HDR) of DSBs. Loss of Polδ4 leads to HDR deficiency and is a novel potential contributor to tumorigenesis. Our goals are directed to the unexplored roles of Polδ4 loss in lung tumorigenesis. Our first aim is to characterize the effects of the lung carcinogens (Cr(VI), BaP and NNK on p12 degradation in lung epithelial cell lines as well as the mechanisms involved in this process. These studies have not been done in non-neoplastically transformed cells. We will study the potential of chronic exposure to the above-mentioned carcinogens on p12 degradation, as well as their capacity to lead to epigenetic changes that suppress p12 expression after chronic exposure. Our second aim is to test the hypothesis that p12 depletion facilitates neoplastic transformation of lung epithelial cells. We will examine whether p12 deletion promotes neoplastic transformation of lung epithelial cells induced by these carcinogens. We will also investigate whether p12 deletion enhances the ability of urethane to induce lung tumors to provide an in vivo readout of the effects of p12 on lung tumorigenesis. As deletion of p12 eliminates the possibility of forming the Polδ4 enzyme, the p12 knockout cell and mouse models are absent of Polδ4. These models thus have a unique and defined locus in the convergent step of D-loop extension, a crucial step in HDR. The p12 knockout mouse model provides a unique opportunity to examine the role of p12 in lung carcinogenesis induced by genotoxic carcinogens in vivo in a clean background. These studies will lead to evidence for a role of Polδ4 in lung tumorigenesis that originates from a novel route to HR-deficiency and have the potential to open up further avenues of research that could contribute to future therapeutic approaches in lung 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: 2025 ( Subtotal = $247,500 )
2025	2025	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Environmental Health	000	2	5/14/2025	NON-COMPETING CONTINUATION	$247,500
														Subtotal = $247,500

Issue Date FY: 2024 ( Subtotal = $206,198 )
2024	2024	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Environmental Health	000	1	6/17/2024	NEW	$206,198
														Subtotal = $206,198

Grand Total All Awards = $453,698

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The role of DNA Polymerase Delta 4 in Lung Carcinogenesis Induced by Genotoxic Carcinogens

Award Number: R21ES036369

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: 06/18/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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