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An RNA-Dependent Innate Immune Response Pathway to Base-Damaging Chemotherapeutics

Award Number: R01CA282733
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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An RNA-Dependent Innate Immune Response Pathway to Base-Damaging Chemotherapeutics - PROJECT SUMMARY The objective of this proposal is to define the mechanism and functional role of innate immune signaling events during base damaging cancer chemotherapy. These agents induce base damage on RNA as well as DNA. We have recently discovered that cells elicit an RNA-dependent innate immune response upon encountering alkylating agents, which represent one of the most commonly used systemic chemotherapies for cancer treatment. Our preliminary data demonstrates that alkylating agents induce a DAMP (damage associated molecular pattern) response, akin to the signaling observed during viral infection, which is known to impact downstream cellular events such as apoptosis. In contrast to other types of DNA damaging agents, this pathway depends on the RNA-associated DAMP receptor RIG-I and requires spliceosomal activity. Furthermore, we have found that ASCC1, which encodes a protein with a metal-independent RNA phosphoesterase domain, associates with intronic RNAs upon damage and is required for the induction of the DAMP response during alkylation. These and other data strongly suggest a model where spliceosome-associated processing of damaged RNA activates DAMP signaling, and may have functional consequences for tumor cell fate upon base damage. In this proposal, we will determine the mechanism by which ASCC1 functions with its associated partner proteins to gain access to damaged nascent RNAs and process them as part of this response, and determine the function consequence of this signaling pathway (Aim 1). In turn, we will characterize the RNA structures that activate RIG-I during alkylation stress and reconstitute RIG-I signaling with purified components (Aim 2). Together, these studies will shed light on a hitherto undescribed mechanism by which a nuclear RNA quality control pathway is connected to innate immune signaling.


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 = $489,536 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	2	2/14/2025	NON-COMPETING CONTINUATION	$440,582
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	001	2	5/21/2025	NON-COMPETING CONTINUATION	$48,954
														Subtotal = $489,536

Issue Date FY: 2024 ( Subtotal = $489,536 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Cause and Prevention Research	000	1	3/15/2024	NEW	$489,536
														Subtotal = $489,536

Grand Total All Awards = $979,072

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An RNA-Dependent Innate Immune Response Pathway to Base-Damaging Chemotherapeutics

Award Number: R01CA282733

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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