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A novel cilium-to-nucleus axis promotes cellular senescence

Award Number: R01AG076469
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: 02/28/2027

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A novel cilium-to-nucleus axis promotes cellular senescence - Project Summary Cellular senescence is a programmed growth arrest activated by irreparable extrinsic or intrinsic stresses. Senescence can be beneficial in certain circumstances, such as tissue homeostasis during embryonic development or tumor suppression. However, if persistently secreted by senescent cells, the proinflammatory cytokines, chemokines, proteases, and growth factors are actually major drivers for aging and age-associated diseases and, paradoxically, promote tumorigenesis. Genetic or pharmacological clearance of senescent cells effectively improves lifespan and healthspan in rodent models. As such, targeting senescence has emerged as a promising therapeutic strategy to prevent or treat aging comorbidities and cancer. However, how the irreversible senescence program is induced and maintained in stressed cells remains poorly understood. Cells utilize primary cilia to convert environmental cues into diverse cellular signalings that govern proliferation, differentiation, and tissue homeostasis. Cilia dysfunction leads to a wide spectrum of syndromic disorders that are collectively termed ciliopathies. Using irradiation, we discovered that stressed human fibroblasts or epithelial cells exhibit transient cilia biogenesis. Strikingly, FBF1, a component of transition fibers (TFs) at the ciliary base, unexpectedly translocates to promyelocytic leukaemia nuclear bodies (PML-NBs) in stressed cells. PML-NBs are highly dynamic proteinaceous nuclear structures with instrumental roles in regulating stress-induced responses, including senescence and apoptosis. FBF1 depletion effectively abolishes stress-induced PML-NB upregulation and associated senescence initiation, whereas FBF1 overexpression shows the opposite effects. Our initial studies indicated that the stress-induced PML-NB translocation of FBF1 is regulated by a distinct cilia module comprising Joubert syndrome proteins ARL3 and ARL13B and the SUMO-conjugating enzyme UBC9. Further proteomic studies revealed novel FBF1 interactors (PML, 53BP1, and BRD4) implicated in PML-NB biogenesis and/or function. Remarkably, Fbf1tm1a/tm1a mice exhibit a significantly reduced senescence burden throughout life and could be further protected against irradiation-induced frailty. Our preliminary data thus suggest an exciting paradigm that a stress-induced TF-to-PML-NB translocation of ciliary protein FBF1 is essential for senescence initiation in mammalian cells. Here, we propose to use complementary approaches to address mechanistic questions, including how the ciliary ARL3-ARL13B-UBC9 module regulates FBF1 SUMOylation and PML-NB translocation (Aim 1), and how PML-NB-associated FBF1 promotes senescence in stressed cells (Aim 2). Together with the extended analysis of the physiological importance of FBF1 pathway in in vivo senescence mouse models (Aim 3), this project will potentially bridge the fundamental discovery to the next generation of therapeutic strategies for preventing or treating senescence-associated pathologies.


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 = $293,355 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	5	2/2/2026	NON-COMPETING CONTINUATION	$293,355
														Subtotal = $293,355

Issue Date FY: 2025 ( Subtotal = $319,431 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	4	6/17/2025	NON-COMPETING CONTINUATION	$26,076
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	4	3/6/2025	NON-COMPETING CONTINUATION	$293,355
														Subtotal = $319,431

Issue Date FY: 2024 ( Subtotal = $325,950 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	002	3	7/3/2024	NON-COMPETING CONTINUATION	$32,595
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	3	2/21/2024	NON-COMPETING CONTINUATION	$293,355
2024	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	2	11/8/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $325,950

Issue Date FY: 2023 ( Subtotal = $325,950 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	2	1/24/2023	NON-COMPETING CONTINUATION	$325,950
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	2	7/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $325,950

Issue Date FY: 2022 ( Subtotal = $325,950 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	1	5/25/2022	NEW	$325,950
														Subtotal = $325,950

Grand Total All Awards = $1,590,636

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A novel cilium-to-nucleus axis promotes cellular senescence

Award Number: R01AG076469

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: 02/28/2027

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