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Repair of Genome Destabilizing DNA Structures

Award Number: R01CA093729
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/28/2002
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Repair of Genome Destabilizing DNA Structures - PROJECT SUMMARY Cancer incidence increases with age in a tissue-specific fashion. Genetic instability and epigenetic alterations (e.g., cytosine methylation) are hallmarks of both cancer etiology and aging, thus linking aging to cancer. Importantly, alternative DNA structure-forming sequences (i.e., non-B DNA) have been identified as endogenous mutation hotspots associated with cancer etiology in an age-related and tissue-specific fashion. Further, methylation can impact non-B DNA formation, its mutagenic potential, and DNA repair mechanisms; and the mutagenic processing of non-B DNA requires DNA repair proteins. However, the mechanisms involved in the age-related and tissue-specific generation of these mutation “hotspots” remain largely unknown. With the aging population increasing, there is a critical need to fill this fundamental gap in knowledge. Our long-term goal is to elucidate the mechanisms of age-associated, tissue-specific DNA structure-induced genetic instability to guide future studies to develop new strategies to prevent and/or treat cancer. Thus, the overall objective of this application is to determine the mechanisms involved in differential DNA structure-induced genetic instability with age and tissue type to inform on cancer etiology. We will test the novel hypothesis that the formation of non-B DNA and their mutagenic processing differ with age in a tissue-specific fashion due to alterations in DNA repair processing and cytosine methylation. The rationale is that determining the mechanisms associated with age-related, tissue-specific DNA structure-induced genetic instability will offer a novel scientific framework whereby new strategies to prevent and/or treat age-associated diseases, such as cancer, can be developed. The hypothesis will be tested in the following aims: 1) Measure the amount of non-B DNA formed and its mutagenic potential with age in mouse tissues; 2) determine age- and tissue-associated alterations in cytosine methylation that alter non-B DNA structure formation and mutagenesis; and 3) identify the DNA repair-associated mechanisms of mutagenic processing of endogenous mutation hotspots with age in mice. Novel mutation-reporter mice containing human non-B DNA sequences from cancer-associated mutation hotspots will be used to determine the effects of age and tissue type on the mutagenic processing of non-B DNA. This is innovative because it will test the novel hypothesis that DNA structure-induced genetic instability is altered with age and tissue type in mammals, dependent on age-related modulations in epigenetics and DNA repair. The expected contribution is the elucidation of the impact of age and tissue type on DNA structure- induced genetic instability, which is significant because the results will inform on the etiology of various cancer types with age. This is expected to have a significant positive impact because the results will help achieve our long-term goal to understand the mechanisms of age-associated, DNA structure-induced genetic instability in various tissues to guide future studies to develop new strategies to prevent and/or treat 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 = $389,019 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	001	24	5/30/2025	NON-COMPETING CONTINUATION	$38,902
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	000	24	1/13/2025	NON-COMPETING CONTINUATION	$350,117
														Subtotal = $389,019

Issue Date FY: 2024 ( Subtotal = $369,568 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	002	23	12/27/2023	NON-COMPETING CONTINUATION	$350,117
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	003	23	4/17/2024	NON-COMPETING CONTINUATION	$19,451
2024	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	001	22	12/19/2023	COMPETING CONTINUATION	$85,086
2024	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	000	21	12/19/2023	NON-COMPETING CONTINUATION	-$85,086
														Subtotal = $369,568

Issue Date FY: 2023 ( Subtotal = $389,019 )
2023	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	001	22	1/27/2023	COMPETING CONTINUATION	$389,019
2023	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	000	21	1/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $389,019

Issue Date FY: 2022 ( Subtotal = $321,791 )
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	000	21	1/10/2022	NON-COMPETING CONTINUATION	$295,523
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	001	21	5/23/2022	NON-COMPETING CONTINUATION	$26,268
														Subtotal = $321,791

Issue Date FY: 2021 ( Subtotal = $328,359 )
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	000	20	12/3/2020	NON-COMPETING CONTINUATION	$311,940
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	001	20	1/21/2021	NON-COMPETING CONTINUATION	$16,419
														Subtotal = $328,359

Issue Date FY: 2020 ( Subtotal = $328,359 )
2020	2020	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	000	19	3/5/2020	NON-COMPETING CONTINUATION	$328,359
														Subtotal = $328,359

Issue Date FY: 2019 ( Subtotal = $318,507 )
2019	2019	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	000	18	12/14/2018	NON-COMPETING CONTINUATION	$318,507
														Subtotal = $318,507

Issue Date FY: 2018 ( Subtotal = $328,359 )
2018	2018	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	001	17	12/11/2017	COMPETING CONTINUATION	$328,359
2018	2018	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	003	17	5/16/2018	COMPETING CONTINUATION	$88,644
2018	2017	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	000	16	12/11/2017	NON-COMPETING CONTINUATION	$0
2018	2017	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	002	16	5/16/2018	NON-COMPETING CONTINUATION	-$88,644
														Subtotal = $328,359

Issue Date FY: 2017 ( Subtotal = $308,158 )
2017	2017	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	001	16	6/7/2017	NON-COMPETING CONTINUATION	$30,817
2017	2017	UNIVERSITY OF TEXAS AT AUSTIN	101 EAST 27TH STREET STE 4308	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	000	16	11/17/2016	NON-COMPETING CONTINUATION	$277,341
														Subtotal = $308,158

Issue Date FY: 2016 ( Subtotal = $308,158 )
2016	2016	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Cancer Cause and Prevention Research	000	15	1/19/2016	EXTENSION WITH OR WITHOUT FUNDS	$308,158
														Subtotal = $308,158

Issue Date FY: 2015 ( Subtotal = $308,158 )
2015	2015	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Cancer Cause and Prevention Research	001	14	1/29/2015	NON-COMPETING CONTINUATION	$30,817
2015	2015	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Cancer Cause and Prevention Research	000	14	12/19/2014	NON-COMPETING CONTINUATION	$277,341
														Subtotal = $308,158

Issue Date FY: 2014 ( Subtotal = $298,913 )
2014	2014	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Cancer Cause and Prevention Research	001	13	5/8/2014	NON-COMPETING CONTINUATION	$21,570
2014	2014	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Cancer Cause and Prevention Research	000	13	12/23/2013	NON-COMPETING CONTINUATION	$277,343
														Subtotal = $298,913

Issue Date FY: 2013 ( Subtotal = $307,493 )
2013	2013	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Cancer Cause and Prevention Research	002	12	6/6/2013	COMPETING CONTINUATION	$153,747
2013	2013	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Cancer Cause and Prevention Research	001	12	12/5/2012	COMPETING CONTINUATION	$153,746
2013	2012	UNIVERSITY OF TEXAS AT AUSTIN	COLLEGE OF PHARMACY	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	000	11	12/3/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $307,493

Issue Date FY: 2012 ( Subtotal = $306,828 )
2012	2012	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Cancer Cause and Prevention Research	001	11	12/30/2011	NON-COMPETING CONTINUATION	$276,112
2012	2012	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Cancer Cause and Prevention Research	002	11	4/26/2012	NON-COMPETING CONTINUATION	$30,716
2012	2009	UNIVERSITY OF TEXAS AT AUSTIN	COLLEGE OF PHARMACY	AUSTIN	TX	78712	TRAVIS	USA	Trans-NIH Recovery Act Research Support	000	10	10/21/2011	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $306,828

Issue Date FY: 2011 ( Subtotal = -$18,828 ) (Continued on the next page)
2011	2010	UNIVERSITY OF TEXAS AT AUSTIN	COLLEGE OF PHARMACY	AUSTIN	TX	78712	TRAVIS	USA	Cancer Cause and Prevention Research	004	10	9/1/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2011	2010	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Cancer Cause and Prevention Research	001	10	6/1/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$306,828
2011	2010	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	9	6/1/2011	NON-COMPETING CONTINUATION	-$306,828
2011	2009	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Trans-NIH Recovery Act Research Support	003	8	7/19/2011	SUPPLEMENT FOR EXPANSION	-$197,600
Grand Total All Awards = $7,843,323

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Repair of Genome Destabilizing DNA Structures

Award Number: R01CA093729

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/28/2002

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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