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Regulatory Mechanisms Governing BubR1 Protein Stability During Stress and Aging

Award Number: R01AG077574
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Regulatory Mechanisms Governing BubR1 Protein Stability During Stress and Aging - Abstract: BubR1 is a key regulator of aging through suppressing cellular senescence and is a critical tumor suppressor through its role in maintaining genome integrity by sustaining fidelity in chromosomal segregation during mitosis through control of the spindle assembly checkpoint. Importantly, BubR1 levels decline with age putting it at the intersection of aging and age-related diseases such as cancer. Loss of BubR1 with age is attributed, in part, through its increased ubiquitin-proteasomal mediated degradation, which can be blocked by increasing the activity of the NAD+-dependent deacetylase SIRT2. However, the E3 ubiquitin ligase(s) involved in promoting the decline in BubR1 with age and under conditions of stress remain elusive. We identified the Skp1-Cullin-F-box (SCF) E3 ubiquitin ligase substrate recognition subunit -TRCP1 as an interactor of BubR1, which targets BubR1 for ubiquitination and degradation. BubR1 contains a putative binding domain for -TRCP1 (known as a degron motif), which lies adjacent to the acetylated lysine controlled by SIRT2 suggesting a cross talk between SIRT2-regulated acetylation and ubiquitination of BubR1 by - TRCP1. Furthermore, -TRCP1 is involved in ubiquitination and degradation of key regulators of genome stability and cancer such as CHK1 and Cyclin D1 in response to cellular stress, including nutrient deprivation. Similarly, BubR1 protein levels are destabilized in response to glucose deprivation, suggesting a putative role for -TRCP1 in regulating BubR1 under physiological stress conditions as well as during the natural aging process. Based on these observations, we hypothesize that -TRCP1 is a key regulator of BubR1 protein stability to control aging and disease. To test this hypothesis, we developed two specific aims. In aim 1 we will define the posttranslational regulation of BubR1 by -TRCP1 at the molecular level, and its impact on cellular senescence and organismal lifespan. These studies will investigate the upstream and downstream pathways by which -TRCP regulates BubR1 protein stability, and its involvement in the promoting the decline of BubR1 with age. In aim 2 we will determine the role of -TRCP1-mediated protein degradation of BubR1 under conditions of cellular stress including glucose deprivation by delineating the molecular mechanisms linking cellular sensing of nutrient stress to ubiquitin-proteasomal mediated degradation of BubR1. In addition, we will assess the consequences of altering BubR1 and other regulators of genome stability in the cellular response to glucose restrictive conditions. Finally, we will elucidate the role of -TRCP1 in proteome remodeling during the cellular response to glucose restriction conditions using an unbiased proteomics-based interaction screen. The overall goal of this proposal is to elucidate at the molecular and cellular level the role of -TRCP in controlling key regulators of genomic stability including BubR1 during cellular stress in aging and disease, which will provide the impetus to develop novel therapeutic interventions for aging and age-related diseases through stabilization of BubR1.


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 = $292,310 )
2025	2025	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Aging Research	000	4	3/25/2025	NON-COMPETING CONTINUATION	$268,448
2025	2025	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Aging Research	001	4	6/18/2025	NON-COMPETING CONTINUATION	$23,862
														Subtotal = $292,310

Issue Date FY: 2024 ( Subtotal = $298,275 )
2024	2024	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Aging Research	000	3	5/7/2024	NON-COMPETING CONTINUATION	$298,275
														Subtotal = $298,275

Issue Date FY: 2023 ( Subtotal = $298,275 )
2023	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Aging Research	000	2	4/12/2023	NON-COMPETING CONTINUATION	$298,275
														Subtotal = $298,275

Issue Date FY: 2022 ( Subtotal = $298,275 )
2022	2022	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Aging Research	000	1	5/19/2022	NEW	$298,275
														Subtotal = $298,275

Grand Total All Awards = $1,187,135

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Regulatory Mechanisms Governing BubR1 Protein Stability During Stress and Aging

Award Number: R01AG077574

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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