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Defining the molecular basis of oncogene-induced replication stress

Award Number: R01ES031658
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: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Defining the molecular basis of oncogene-induced replication stress - PROJECT SUMMARY/ABSTRACT Environmental genotoxic carcinogens target numerous proto-oncogenes (and tumor-suppressor genes) to induce point mutations in key codons, leading to oncogene activation. Oncogene activation disturbs a wide range of cellular processes, including alterations in the genomic and molecular landscape of precancerous cells that contributes to genomic instability, which accelerates chromosomal breakages, rearrangements and promotes tumorigenesis. Part of this cellular turmoil involves early deregulation of physiologic DNA replication, known as replication stress. Oncogene-induced replication stress is an early driver of genomic instability and is attributed to a plethora of factors, most notably aberrant origin firing, replication-transcription collisions, and defective nucleotide metabolism. Despite much progress in the field, the mechanisms through which oncogenes induce replication stress, particularly in early events leading to carcinogenesis, remains poorly understood. Major gaps in our knowledge of this process include: 1) What are the early steps that contributes to oncogene-induced replication stress in precancerous cells? and 2) How are replication stress response factors coordinated to overcome/resolve replication stress in a time-dependent manner? Research into these questions have been hampered by limitations inherent in using traditional cancer cell lines and cell biological approaches that may or may not accurately reflect the temporal and spatial regulation of the DNA replication stress response in a more physiologically-relevant in vitro pre-cancer model. In this application, we propose to address these knowledge gaps by using cancer-relevant primary human cells to explore how oncogene-induced replication stress can shape genome-wide replication fork initiation and termination sites, focusing on how these changes in the replication program will impact genome integrity. Furthermore, we will determine how recently discovered players in the replication stress response pathway are regulated to subvert oncogene-induced replication stress. Deciphering the mechanisms that contribute to this early replication stress response at the genome-wide level may provide new avenues for targeted cancer treatment. The questions we address here will set the stage for future investigations that include (but are not limited to) analyses of how environmental genotoxins may influence oncogene-induced replication stress to exacerbate genomic instability to accelerate tumorigenesis.


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 = $419,343 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	000	5	11/1/2024	NON-COMPETING CONTINUATION	$419,343
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	001	5	9/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $419,343

Issue Date FY: 2024 ( Subtotal = $426,547 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	000	4	10/26/2023	NON-COMPETING CONTINUATION	$426,547
														Subtotal = $426,547

Issue Date FY: 2023 ( Subtotal = $433,750 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	000	3	10/31/2022	NON-COMPETING CONTINUATION	$433,750
														Subtotal = $433,750

Issue Date FY: 2022 ( Subtotal = $440,954 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	000	2	10/27/2021	NON-COMPETING CONTINUATION	$440,954
														Subtotal = $440,954

Issue Date FY: 2021 ( Subtotal = $448,158 )
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	000	1	1/18/2021	NEW	$448,158
														Subtotal = $448,158

Grand Total All Awards = $2,168,752

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Defining the molecular basis of oncogene-induced replication stress

Award Number: R01ES031658

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: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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