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Characterizing the LINE-1 Retrotransposition-Replication Conflict

Award Number: R01CA240816
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Characterizing the LINE-1 Retrotransposition-Replication Conflict - Project Summary Much of our genome is made up of interspersed repeats derived from the activities of mobile genetic elements. There are subsets of these sequences that become activated in cancers. Our research lab and others have shown that nearly half of cancers fail to restrain long interspersed element-1 (LINE-1, L1) sequences. L1 is an active retrotransposon that codes for two proteins, an RNA binding protein (ORF1p) and a protein with endonuclease and reverse transcriptase activities (ORF2p). Paradoxically, though these proteins are pervasively expressed in many human cancers, they inhibit cell growth in culture. We have exciting new data from genome-wide knockout screens demonstrating how tumor suppressor gene mutations found in cancers enable them to survive and grow despite their expression of L1. More importantly, these screens have also identified genes that become essential in cells coping with L1 expression. These synthetic lethal genes represent unique molecular vulnerabilities for L1(+) cells. L1(+) cells require specific DNA repair pathways, effective replication stress signaling pathways, and replication fork restart capabilities. Here, we will test the hypothesis that these pathways are required to eliminate L1 insertion intermediates and prevent collisions between these intermediates and DNA replication forks. This project will increase our understanding of how cancer cells replicate their DNA. It could lay a foundation to leverage L1-associated DNA replication stress to limit cancer cell growth.


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: 2026 ( Subtotal = $0 )
2026	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Cause and Prevention Research	000	5	11/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $384,644 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Cause and Prevention Research	000	5	6/28/2024	NON-COMPETING CONTINUATION	$384,644
														Subtotal = $384,644

Issue Date FY: 2023 ( Subtotal = $396,790 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	4	6/1/2023	NON-COMPETING CONTINUATION	$396,790
														Subtotal = $396,790

Issue Date FY: 2022 ( Subtotal = $396,790 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	3	6/3/2022	NON-COMPETING CONTINUATION	$396,790
														Subtotal = $396,790

Issue Date FY: 2021 ( Subtotal = $404,888 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	2	6/29/2021	NON-COMPETING CONTINUATION	$404,888
														Subtotal = $404,888

Issue Date FY: 2020 ( Subtotal = $404,888 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	1	7/13/2020	NEW	$404,888
														Subtotal = $404,888

Grand Total All Awards = $1,988,000

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Characterizing the LINE-1 Retrotransposition-Replication Conflict

Award Number: R01CA240816

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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