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Mechanism of the telomeric proliferation limit

Award Number: R01AG016642
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/1999
PERIOD OF PERFORMANCE END DATE: 03/31/2025

Group Awards By:

View Award Description

Mechanism of the telomeric proliferation limit - Project Summary/Abstract This project focuses on the biology of telomeres, the protective elements at chromosome ends whose erosion limits the replicative lifespan of primary human cells. Telomere dysfunction has been implicated in a number of human diseases, including inherited bone marrow failure syndromes and cancer. We aim to understand how telomeres protect chromosome ends and how they are maintained. Insights into these issues resulted from our studies of shelterin, the six-subunit protein complex that binds to telomeric DNA. Shelterin is anchored on telomeres by two telomeric DNA binding proteins, TRF1 and TRF2, which promote telomere replication and protect telomeres from the DNA damage response, respectively. This proposal focuses on these two critical telomere factors. In AIM 1, we will critically test the leading model in the field that telomeres are protected through the formation of the t-loop structure by TRF2. We have previously shown that TRF2 is required for t-loop formation and our preliminary data indicates that TRF2 is sufficient to create this structure. Despite the popularity of this model, there is no direct proof that t-loops repress the DNA damage response. We are developing orthogonal (TRF2-independent) tools for t-loop formation and will test whether generation of t-loops is sufficient to repress the DNA damage response in absence of TRF2. In AIM 2, we will investigate how TRF2 generates t- loops. T-loop formation is thought to require the TRFH domain of TRF2 but how this domain acts is not clear. Our preliminary studies of the TRFH domains of TRF2 (which forms t-loops) and TRF1 (which does not) have identified features of the TRF2 TRFH domain with potential relevance to t-loop formation. These attributes will be tested for their relevance to telomere protection in vivo. In AIM 3, we will study the role of the TRF2 Myb domain in the protection of telomeres. Our preliminary data challenge the widely-held view that the TRF1/2 Myb domains only function as DNA binding modules and suggest that they have additional functions, potentially through protein-protein interactions. We will pursue our hypothesis, based on our preliminary data, that the Myb domain of TRF2 mediates a critical role in telomere protection. In AIM 4, we will investigate the function of TRF1 in telomere replication. Loss of TRF1 induces fragile telomeres, replication fork stalling, and sister telomere associations. Our preliminary data show how TRF1 uses the BLM helicase to prevent lagging-strand replication problems, most likely caused by G4 DNA. We propose to investigate how TRF1 prevents leading-strand replication problems, fork stalling, and sister telomere associations. We will expand on our preliminary data indicating that the sister telomere associations represent a novel type of telomere fusion resulting from a previously unrecognized alt-NHEJ mechanism involving stalled replication forks. This project will use innovative approaches and our established biochemical, cell biological, and molecular genetic tools to reveal new concepts in telomere biology with relevance to age-related human disease states.


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 = $526,260 )
2026	2026	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	001	27	7/10/2026	NON-COMPETING CONTINUATION	$526,260
2026	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	25	1/19/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $526,260

Issue Date FY: 2025 ( Subtotal = $522,896 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	001	26	7/30/2025	COMPETING CONTINUATION	$522,896
2025	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	25	7/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $522,896

Issue Date FY: 2024 ( Subtotal = $487,055 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	25	3/1/2024	NON-COMPETING CONTINUATION	$438,350
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	001	25	6/25/2024	NON-COMPETING CONTINUATION	$48,705
														Subtotal = $487,055

Issue Date FY: 2023 ( Subtotal = $487,055 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	24	4/4/2023	NON-COMPETING CONTINUATION	$487,055
														Subtotal = $487,055

Issue Date FY: 2022 ( Subtotal = $487,055 )
2022	2022	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	23	4/13/2022	NON-COMPETING CONTINUATION	$487,055
														Subtotal = $487,055

Issue Date FY: 2021 ( Subtotal = $487,056 )
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	001	22	3/12/2021	NON-COMPETING CONTINUATION	$97,553
2021	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	21	10/30/2020	COMPETING CONTINUATION	$389,503
														Subtotal = $487,056

Issue Date FY: 2020 ( Subtotal = $487,055 )
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	001	21	3/27/2020	COMPETING CONTINUATION	$487,055
2020	2018	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	20	1/31/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $487,055

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	20	8/20/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $587,892 )
2018	2018	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	20	5/3/2018	NON-COMPETING CONTINUATION	$587,892
														Subtotal = $587,892

Issue Date FY: 2017 ( Subtotal = $587,892 )
2017	2017	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	001	19	6/21/2017	NON-COMPETING CONTINUATION	$58,788
2017	2017	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	19	4/28/2017	NON-COMPETING CONTINUATION	$529,104
														Subtotal = $587,892

Issue Date FY: 2016 ( Subtotal = $587,892 )
2016	2016	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	18	4/27/2016	NON-COMPETING CONTINUATION	$587,892
														Subtotal = $587,892

Issue Date FY: 2015 ( Subtotal = $570,256 )
2015	2015	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	17	3/18/2015	NON-COMPETING CONTINUATION	$570,256
														Subtotal = $570,256

Issue Date FY: 2014 ( Subtotal = $618,270 )
2014	2014	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	001	16	8/28/2014	COMPETING CONTINUATION	$618,270
2014	2013	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	15	8/25/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $618,270

Issue Date FY: 2013 ( Subtotal = $466,509 )
2013	2013	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	15	6/20/2013	NON-COMPETING CONTINUATION	$466,509
														Subtotal = $466,509

Issue Date FY: 2012 ( Subtotal = $494,072 )
2012	2012	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	14	5/23/2012	NON-COMPETING CONTINUATION	$494,072
														Subtotal = $494,072

Issue Date FY: 2011 ( Subtotal = $493,480 )
2011	2011	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	13	6/30/2011	NON-COMPETING CONTINUATION	$493,480
														Subtotal = $493,480

Issue Date FY: 2010 ( Subtotal = $498,004 )
2010	2010	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	12	6/24/2010	NON-COMPETING CONTINUATION	$498,004
														Subtotal = $498,004

Issue Date FY: 2009 ( Subtotal = $510,708 )
2009	2009	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	001	11	8/12/2009	COMPETING CONTINUATION	$510,708
2009	2008	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	10	8/12/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $510,708

Issue Date FY: 2008 ( Subtotal = $392,986 )
2008	2008	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	10	6/19/2008	NON-COMPETING CONTINUATION	$392,986
														Subtotal = $392,986

Issue Date FY: 2007 ( Subtotal = $401,007 )
2007	2007	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	9	6/29/2007	NON-COMPETING CONTINUATION	$401,007
														Subtotal = $401,007

Issue Date FY: 2006 ( Subtotal = $412,984 )
2006	2006	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	8	7/13/2006	NON-COMPETING CONTINUATION	$412,984
														Subtotal = $412,984

Grand Total All Awards = $12,575,684

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Mechanism of the telomeric proliferation limit

Award Number: R01AG016642

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/1999

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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