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Ubiquitin‐mediated proteolysis and cell cycle control

Award Number: R01AG011085
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/1997
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Ubiquitin‐mediated proteolysis and cell cycle control - PROJECT SUMMARY CULLIN-RING E3 ubiquitin ligases (CRLs) employ ~200 adaptor proteins to bind and ubiquitylate substrates, and their dynamic assembly with adaptor proteins is regulated by the neddylation cycle together with the CAND adaptor exchange factor. Several CRLs have been linked with turnover of proteins involved in aging, cell cycle control, DNA repair, transcription, and cellular signaling pathways. Despite these advances, our understanding of the CRL system is incomplete for several reasons. First, the majority of studies on CRLs have focused on the functions of a small number of well-studied adaptors. As such, we have a limited understanding of the targets and biological functions for a substantial portion of the CRL system. Second, the many studies have been performed in cancer cell lines, leaving open the roles of these proteins in a more physiological setting. Third, many adaptors likely have multiple substrates and function through structurally related degrons in diverse substrates, yet we do not understand the biochemistry of degron targeting for the majority of adaptors. Such information can broadly inform discovery of biological functions, as has been the case for a small number of CRL adaptors such as TRCP. To bridge these knowledge gaps, our work has focused on the development of genetic methods to rapidly identify CRL adaptor targets and cognate degron sequences in substrates, and on the development of proteomic approaches that allow global quantification of proteome remodeling in response to cellular, genetic, or chemical cues. In AIM 1, we build on our discovery of 10 N/C-End E3 ubiquitin ligases that recognize their targets based on sequences at their N or C-termini to systematically elucidate their targets and roles in proteome remodeling as cells undergo differentiation to germ cell lineages. Human stem cell differentiation to germ cell lineages is associated with alterations in the abundance of >30% of the proteome, and we propose that N/C-End E3s play a central role in proteome remodeling, in part via quality control dependent protein degradation. This aim also builds on our extensive characterization of CRLs in this system, and on the development of multiple proteomic methods that provide a quantitative understanding of protein turnover and remodeling during changes in cell state. In AIMs 2 and 3, we further develop an experimental platform for genetic discovery of CRL targets and degrons (including regulated phosphodegrons), as well as matching of substrates and degrons with specific CRL adaptors. We provide examples of how these two platforms have resulted in the mechanistic dissection of new pathways for turnover of key transcription factors involved in nutrient signaling and propose to analyze newly discovered substrate-E3 pairs using systematic biochemical and cell biological approaches. Our expectation is that these studies will substantially advance our understanding of the molecular determinants in CRL dependent protein degradation and will provide unique insights into mechanisms underlying proteome remodeling during changes in cell state.


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 = $491,380 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	002	32	4/2/2025	NON-COMPETING CONTINUATION	$451,268
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	003	32	6/10/2025	NON-COMPETING CONTINUATION	$40,112
2025	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	30	2/18/2025	COMPETING CONTINUATION	$19,584
2025	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	29	2/18/2025	NON-COMPETING CONTINUATION	-$19,584
														Subtotal = $491,380

Issue Date FY: 2024 ( Subtotal = $489,225 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	31	4/30/2024	NON-COMPETING CONTINUATION	$489,225
														Subtotal = $489,225

Issue Date FY: 2023 ( Subtotal = $504,318 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	30	4/28/2023	COMPETING CONTINUATION	$504,318
														Subtotal = $504,318

Issue Date FY: 2022 ( Subtotal = $460,839 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	29	6/9/2022	NON-COMPETING CONTINUATION	$460,839
														Subtotal = $460,839

Issue Date FY: 2021 ( Subtotal = $465,972 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	28	6/23/2021	NON-COMPETING CONTINUATION	$465,972
														Subtotal = $465,972

Issue Date FY: 2020 ( Subtotal = $470,820 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	27	6/23/2020	NON-COMPETING CONTINUATION	$470,820
														Subtotal = $470,820

Issue Date FY: 2019 ( Subtotal = $477,801 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	26	5/3/2019	NON-COMPETING CONTINUATION	$477,801
														Subtotal = $477,801

Issue Date FY: 2018 ( Subtotal = $499,936 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	25	5/31/2018	COMPETING CONTINUATION	$467,035
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	003	25	9/28/2018	COMPETING CONTINUATION	$35,803
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	25	8/31/2018	COMPETING CONTINUATION	$32,901
2018	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	002	24	9/28/2018	NON-COMPETING CONTINUATION	-$35,803
														Subtotal = $499,936

Issue Date FY: 2017 ( Subtotal = $402,786 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	003	24	6/23/2017	NON-COMPETING CONTINUATION	$351,365
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	004	24	7/20/2017	NON-COMPETING CONTINUATION	$51,438
2017	2016	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	23	10/24/2016	EXTENSION WITH OR WITHOUT FUNDS	$31,161
2017	2015	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	22	10/24/2016	NON-COMPETING CONTINUATION	-$31,161
2017	2012	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	002	19	5/8/2017	NON-COMPETING CONTINUATION	-$17
														Subtotal = $402,786

Issue Date FY: 2016 ( Subtotal = $395,546 )
2016	2016	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	23	5/30/2016	EXTENSION WITH OR WITHOUT FUNDS	$395,546
														Subtotal = $395,546

Issue Date FY: 2015 ( Subtotal = $377,361 )
2015	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	22	6/8/2015	NON-COMPETING CONTINUATION	$377,361
														Subtotal = $377,361

Issue Date FY: 2014 ( Subtotal = $389,947 )
2014	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	21	6/14/2014	NON-COMPETING CONTINUATION	$389,947
														Subtotal = $389,947

Issue Date FY: 2013 ( Subtotal = $409,191 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	20	8/19/2013	COMPETING CONTINUATION	$409,191
2013	2012	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	19	8/16/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $409,191

Issue Date FY: 2012 ( Subtotal = $424,049 )
2012	2012	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	19	2/2/2012	NON-COMPETING CONTINUATION	$424,049
														Subtotal = $424,049

Issue Date FY: 2011 ( Subtotal = $425,902 )
2011	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	18	6/20/2011	NON-COMPETING CONTINUATION	$27,117
2011	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	18	2/3/2011	NON-COMPETING CONTINUATION	$398,785
														Subtotal = $425,902

Issue Date FY: 2010 ( Subtotal = $431,732 )
2010	2010	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	17	2/12/2010	NON-COMPETING CONTINUATION	$431,732
														Subtotal = $431,732

Issue Date FY: 2009 ( Subtotal = $423,500 )
2009	2009	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	16	3/25/2009	NON-COMPETING CONTINUATION	$423,500
														Subtotal = $423,500

Issue Date FY: 2008 ( Subtotal = $383,718 )
2008	2008	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	15	2/14/2008	COMPETING CONTINUATION	$383,718
														Subtotal = $383,718

Issue Date FY: 2006 ( Subtotal = $413,792 )
2006	2006	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	14	3/21/2006	NON-COMPETING CONTINUATION	$413,792
														Subtotal = $413,792

Grand Total All Awards = $10,907,426

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Ubiquitin‐mediated proteolysis and cell cycle control

Award Number: R01AG011085

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/1997

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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