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Structural biology of telomerase and telomeres

Award Number: R35GM131901
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: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Structural biology of telomerase and telomeres - Project Summary/Abstract Telomeres, the physical ends of linear chromosomes, are composed of short repeating sequences (TTGGGG in the G-strand for Tetrahymena thermophila and TTAGGG in human) of double-strand DNA with a single-strand 3′ overhang of the G-strand and, in humans, six proteins collectively called shelterin. Of these, TPP1–POT1 associate with the 3′ overhang, where POT1 binds the G-strand and TPP1 functions to recruit telomerase via interaction with telomerase reverse transcriptase (TERT). The telomere DNA 3’-ends are replicated and maintained by telomerase, for the G-strand and subsequently DNA polymerase α–primase (PolαPrim) in complex with CTC1–STN1–TEN1 (CST), for the C-strand. In Tetrahymena, orthologous proteins p50 (TPP1), Teb1 (POT1), and CST are constitutively associated with telomerase. Mutations that affect their activity or regulation have profound effects on human health. Recent cryoEM structures and other studies on Tetrahymena and human telomerase and these interacting partners set the stage for our goals to illuminate the detailed mechanism and regulation of G-strand and C-strand synthesis at telomeres. Our focus will be on two broad aspects of human and Tetrahymena telomerase and telomere structural biology: (A) telomerase mechanism, assembly, and disease and (B) C-strand synthesis by CST–PolαPrim. Our research approach will primarily involve complementary applications of cryoEM and NMR spectroscopy along with rigorous biochemistry and molecular biology. Results on the two organisms will provide complementary information on shared structures and mechanisms while also providing an evolutionary perspective for divergent organisms. Additionally, (C) we will extend from single particle cryoEM to cryoET to visualize telomerase at telomeres in situ.


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 = $695,218 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	4/2/2026	NON-COMPETING CONTINUATION	$695,218
														Subtotal = $695,218

Issue Date FY: 2025 ( Subtotal = $695,218 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	002	7	4/16/2025	NON-COMPETING CONTINUATION	$695,218
2025	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	000	6	11/21/2024	COMPETING CONTINUATION	$0
2025	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	001	5	2/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $695,218

Issue Date FY: 2024 ( Subtotal = $913,201 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	001	6	9/4/2024	SUPPLEMENT FOR EXPANSION	$218,535
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10920 WILSHIRE BLVD STE 500	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	000	6	3/8/2024	COMPETING CONTINUATION	$694,666
														Subtotal = $913,201

Issue Date FY: 2023 ( Subtotal = $625,997 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	3/16/2023	NON-COMPETING CONTINUATION	$625,997
														Subtotal = $625,997

Issue Date FY: 2022 ( Subtotal = $625,997 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	3/16/2022	NON-COMPETING CONTINUATION	$563,392
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biomedical Research and Research Training	001	4	7/22/2022	NON-COMPETING CONTINUATION	$62,605
														Subtotal = $625,997

Issue Date FY: 2021 ( Subtotal = $625,997 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	3/9/2021	NON-COMPETING CONTINUATION	$625,997
														Subtotal = $625,997

Issue Date FY: 2020 ( Subtotal = $616,676 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	3/10/2020	NON-COMPETING CONTINUATION	$616,676
														Subtotal = $616,676

Issue Date FY: 2019 ( Subtotal = $898,592 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	3/29/2019	NEW	$648,592
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biomedical Research and Research Training	001	1	8/27/2019	SUPPLEMENT FOR EXPANSION	$250,000
														Subtotal = $898,592

Grand Total All Awards = $5,696,896

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Structural biology of telomerase and telomeres

Award Number: R35GM131901

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: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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