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Role of TERRA in Telomere Maintenance and Telomere Stress Response

Award Number: R01CA140652
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2010
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Role of TERRA in Telomere Maintenance and Telomere Stress Response - Project Summary Human telomeres are specialized chromatin structures uniquely programmed to coordinate cellular division with genomic integrity, thus providing a senescence barrier to cancer-cell evolution. Telomere structural maintenance and genome sensing functions require extensive epigenetic signaling and higher-order chromatin dynamics that are poorly understood. Our previous studies have revealed the important roles of telomere encoded repeat RNA (TERRA) in the coordinate regulation of telomere chromatin structure, DNA replication and repeat-length maintenance. We have found that TERRA expression can be regulated by subtelomeric binding of chromatin organizing factor CTCF and tumor suppressor protein p53 in response to DNA damage stress. TERRA is also regulated by histone assembly factors DAXX and ATRX that are implicated in the Alternative Lengthening of Telomeres (ALT) through recombination. New preliminary data indicates that DAXX and ATRX are also required for p53 binding to subtelomeres in response to DNA damage, suggesting a coordinate regulation of these factors in telomere chromatin control and TERRA expression. In Aim 1, we investigate the role of DAXX and ATRX in regulating telomeric and subtelomeric chromatin accessibility that is critical for p53 binding, TERRA expression, and telomere DNA repeat stability. TERRA is also known to interact with shelterin component TRF2. In Aim 2, we propose to investigate the interaction of TERRA with the TRF2 amino terminal GAR domain, and how this further regulates telomeric DNA replication, chromatin structure, and chromosome conformation. Finally, in Aim 3, we will investigate how TERRA and telomeric chromatin can be processed into vesicular bodies in response to telomeric stress to generate extracellular inflammatory signals. We propose that exosomal TERRA and telomeric chromatin serve as telomere-specific Alarmins that are important in cellular senescence and tumor microenvironment signaling. These studies will provide an integrated analysis of telomere transcription and chromatin regulation, with stress response pathways that are important in human cancer and related inflammatory disease. Central Hypothesis: Telomeres are specialized epigenetic elements that sense and signal replication stress to control cell proliferative capacity and senescence. TERRA represents an important telomere-repeat generated molecule that functions in chromatin structure, DNA replication and repair, and DNA damage signaling. Characterization of normal and pathogenic functions of TERRA will provide important insight into the mechanisms driving genetic instability in cancer and related genetic instability syndromes.


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 = $434,696 )
2025	2025	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	15	1/13/2025	NON-COMPETING CONTINUATION	$391,227
2025	2025	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	15	5/29/2025	NON-COMPETING CONTINUATION	$43,469
														Subtotal = $434,696

Issue Date FY: 2024 ( Subtotal = $412,961 )
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	14	12/22/2023	NON-COMPETING CONTINUATION	$391,227
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	14	4/18/2024	NON-COMPETING CONTINUATION	$21,734
														Subtotal = $412,961

Issue Date FY: 2023 ( Subtotal = $434,696 )
2023	2023	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	13	2/23/2023	NON-COMPETING CONTINUATION	$426,002
2023	2023	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	13	9/15/2023	NON-COMPETING CONTINUATION	$8,694
														Subtotal = $434,696

Issue Date FY: 2022 ( Subtotal = $426,002 )
2022	2022	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	12	6/21/2022	NON-COMPETING CONTINUATION	$34,776
2022	2022	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	12	1/7/2022	NON-COMPETING CONTINUATION	$391,226
														Subtotal = $426,002

Issue Date FY: 2021 ( Subtotal = $434,696 )
2021	2021	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	11	2/4/2021	COMPETING CONTINUATION	$434,696
2021	2019	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	002	10	6/1/2021	NON-COMPETING CONTINUATION	$0
2021	2019	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	10	1/27/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $434,696

Issue Date FY: 2019 ( Subtotal = $407,400 )
2019	2019	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	10	4/15/2019	NON-COMPETING CONTINUATION	$407,400
														Subtotal = $407,400

Issue Date FY: 2018 ( Subtotal = $420,000 )
2018	2018	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	9	3/20/2018	NON-COMPETING CONTINUATION	$378,000
2018	2018	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	9	5/23/2018	NON-COMPETING CONTINUATION	$42,000
														Subtotal = $420,000

Issue Date FY: 2017 ( Subtotal = $420,000 )
2017	2017	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	8	6/7/2017	NON-COMPETING CONTINUATION	$42,000
2017	2017	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	8	4/27/2017	NON-COMPETING CONTINUATION	$378,000
														Subtotal = $420,000

Issue Date FY: 2016 ( Subtotal = $420,000 )
2016	2016	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	7	4/7/2016	NON-COMPETING CONTINUATION	$420,000
														Subtotal = $420,000

Issue Date FY: 2015 ( Subtotal = $442,500 )
2015	2015	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	6	8/27/2015	COMPETING CONTINUATION	$11,250
2015	2015	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	6	5/19/2015	COMPETING CONTINUATION	$431,250
														Subtotal = $442,500

Issue Date FY: 2014 ( Subtotal = $361,188 )
2014	2014	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	5	5/15/2014	NON-COMPETING CONTINUATION	$361,188
														Subtotal = $361,188

Issue Date FY: 2013 ( Subtotal = $325,422 )
2013	2013	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	4	7/2/2013	NON-COMPETING CONTINUATION	$244,066
2013	2013	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	4	5/1/2013	NON-COMPETING CONTINUATION	$81,356
														Subtotal = $325,422

Issue Date FY: 2012 ( Subtotal = $340,960 )
2012	2012	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	3	4/30/2012	NON-COMPETING CONTINUATION	$340,960
														Subtotal = $340,960

Issue Date FY: 2011 ( Subtotal = $340,960 )
2011	2011	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	2	5/26/2011	NON-COMPETING CONTINUATION	$340,960
														Subtotal = $340,960

Issue Date FY: 2010 ( Subtotal = $351,505 )
2010	2010	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	1	6/29/2010	NEW	$351,505
														Subtotal = $351,505

Grand Total All Awards = $5,972,986

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Role of TERRA in Telomere Maintenance and Telomere Stress Response

Award Number: R01CA140652

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2010

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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