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CRISPR RNA-guided recognition of invading RNA activates a multipronged cell death response

Award Number: F31GM153146
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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CRISPR RNA-guided recognition of invading RNA activates a multipronged cell death response - PROJECT SUMMARY CRISPRs (Clustered, Regularly, Interspersed, Palindromic Repeats) and CRISPR-associated proteins (Cas) are essential components of adaptive immune systems in bacteria and archaea that provide sequence-specific protection from viruses and other genetic parasites. CRISPR systems are phylogenetically and functionally diverse. Most of the work on CRISPR systems has focused on a subset of systems that function as RNA- guided endonucleases that exclusively bind and cleave double-stranded DNA (dsDNA). In all CRISPR subtypes, this RNA guide is derived from the CRISPR loci transcripts and serves as a genetic memory of past infections. The work in this application focuses on determining the structure and function of a unique type III CRISPR system that includes Cas genes that contain domain fusions bearing strong homology to known toxins (HEPN and RelE) and an antitoxin (MntA). Unlike most CRISPR systems, that target DNA, type III CRISPR systems are unique in their utilization of multi-subunit ribonucleoprotein complexes to bind and destroy RNA that is complementary to the CRISPR-RNA guide. In addition to targeting RNA, type III CRISPR systems encode a specialized surveillance complex subunit called Cas10. Target recognition by type III triggers polymerase-cyclase activity in the palm domain of the Cas10 subunit which amplifies the immune response by selectively converting ≈4,000 ATP molecules into cyclic oligoadenylates that function as immune signaling molecules. Using computational methods, the Wiedenheft lab has recently identified a unique subclass of type III-B CRISPRs distributed across three phyla. These type III-B systems have co-opted elements of toxin- antitoxin systems and the immune cassette includes an additional toxin that I predict is regulated by cyclic oligoadenylate signaling. I hypothesize that these type III-B CRISPR-toxin-antitoxin defense systems rely on CRISPR RNA-guided recognition of invading RNA to activate a multipronged cell death response. In Aim 1, I will use cryo-electron microscopy to determine structures of the type III-B surveillance complexes in various states of activation. These structures will provide critical mechanistic insight that explains how different elements of the immune response are regulated by the effector complex. In Aim2, I will determine the mechanisms by which specialized toxins stall viral infections via a CRISPR-controlled collapse of translation. Collectively, these experiments and the associated training objectives outlined in this application will clarify CRISPR-mediated mechanisms that regulate cell death in response to viral infection.


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 = $0 )
2026	2025	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	2	1/23/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $36,479 )
2025	2025	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	2	12/18/2024	NON-COMPETING CONTINUATION	$36,479
														Subtotal = $36,479

Issue Date FY: 2024 ( Subtotal = $36,479 )
2024	2024	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	003	1	6/11/2024	NEW	$1,280
2024	2024	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	002	1	1/1/2024	NEW	$0
2024	2024	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	001	1	1/1/2024	NEW	$0
2024	2024	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	1	1/1/2024	NEW	$35,199
														Subtotal = $36,479

Grand Total All Awards = $72,958

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CRISPR RNA-guided recognition of invading RNA activates a multipronged cell death response

Award Number: F31GM153146

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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