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Suppression of mobile elements by p53 genes

Award Number: R01GM115682
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2015
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Suppression of mobile elements by p53 genes - Summary The p53 gene family occupies central positions in stress response networks throughout the animal kingdom and, as transcription factors, these proteins specify robust adaptive responses. Furthermore, the human counterpart is broadly implicated in age-related diseases including most cancers. Yet despite extensive characterization, disease deterrence by p53 is not well understood and conventional explanations for how p53 prevents oncogenic transformation have been fundamentally challenged. Since p53 genes are broadly conserved, ancestral properties of these genes offer promising routes towards understanding functions that become deranged in human diseases. Toward this goal, we built tools to explore the p53 regulatory network in genetic models, enabling unique opportunities to interrogate conserved properties that support human pathologies. These resources include in vivo biosensors that visualize real-time p53 action and complementation platforms that exchange human alleles for the fly counterpart. Leveraging these tools in flies and in fish, we discovered that p53 is acutely sensitive to - and normally restrains - retrotransposons, which are mobile elements broadly implicated in human disease. Likewise, we further showed that human p53 genes could similarly restrain transposons, but mutated p53 alleles from cancer patients could not. These combined discoveries suggest that p53 acts through highly conserved mechanisms to restrict transposons. Furthermore, since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates disease, in part, by suppressing the activity of transposons. Consistent with this, we exposed hyperactive retrotransposons in p53-driven cancers and found co-repression activity that is obligate for p53 suppression. Initiatives advanced in this proposal build on these discoveries to determine precisely how p53 restrains mobile elements. Our approach integrates genetic models with molecular systems to deconstruct this process. Within this framework, we may deliver new opportunities for improved diagnosis and treatment of conditions fueled by dysfunctional p53.


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: 2024 ( Subtotal = $344,400 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	8	6/25/2024	NON-COMPETING CONTINUATION	$34,440
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	8	11/9/2023	NON-COMPETING CONTINUATION	$309,960
														Subtotal = $344,400

Issue Date FY: 2023 ( Subtotal = $344,400 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	7	11/17/2022	NON-COMPETING CONTINUATION	$309,960
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	7	2/16/2023	NON-COMPETING CONTINUATION	$34,440
														Subtotal = $344,400

Issue Date FY: 2022 ( Subtotal = $344,400 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	6	8/2/2022	NON-COMPETING CONTINUATION	$34,440
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	6	11/10/2021	NON-COMPETING CONTINUATION	$309,960
														Subtotal = $344,400

Issue Date FY: 2021 ( Subtotal = $343,613 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	5	11/30/2020	COMPETING CONTINUATION	$343,613
2021	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	4	11/30/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $343,613

Issue Date FY: 2018 ( Subtotal = $319,950 )
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	4	5/14/2018	NON-COMPETING CONTINUATION	$319,950
														Subtotal = $319,950

Issue Date FY: 2017 ( Subtotal = $319,950 )
2017	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	3	5/25/2017	NON-COMPETING CONTINUATION	$319,950
														Subtotal = $319,950

Issue Date FY: 2016 ( Subtotal = $319,704 )
2016	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	2	5/24/2016	NON-COMPETING CONTINUATION	$319,704
														Subtotal = $319,704

Issue Date FY: 2015 ( Subtotal = $318,963 )
2015	2015	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	1	7/7/2015	NEW	$318,963
														Subtotal = $318,963

Grand Total All Awards = $2,655,380

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Suppression of mobile elements by p53 genes

Award Number: R01GM115682

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2015

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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