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Regulation of APOBEC3 cytidine deaminase-induced mutation during cancerdevelopment

Award Number: R01CA269784
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/06/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Regulation of APOBEC3 cytidine deaminase-induced mutation during cancerdevelopment - Abstract APOBEC signature mutations (C to T and C to G substitutions in TCA and TCT trinucleotide sequences) comprise the second most abundant mutation signature in human cancers. This signature is caused by aberrant activity of several members of the APOBEC family of cytidine deaminases, which normally function in many cellular processes including the restriction of viruses. Recently, we found that APOBEC3A (A3A) expression is elevated in APOBEC-mutated breast cancer cell lines, resulting in increased cellular cytidine deaminase activity and breast cancer mutagenesis. The objectives of this proposal are to characterize newly identified components of the APOBEC mutation signature, determine how A3A mRNA expression is upregulated in cancer, define proteasomal controls on A3A protein abundance, and characterize DNA repair pathways that limit A3A mutagenesis. Aim1 will determine the causes and consequences of A3A- and APOBEC3B-induced insertion/deletion mutations. Aim 2 will characterize the mechanisms leading to aberrant up-regulation of A3A in breast cancers by identifying the transcription factors and signaling pathways responsible for increasing A3A expression. Additionally, we will investigate the mechanism(s) leading to proteasome-dependent degradation of A3A and assess the mutagenic consequences of defective post- translational control of A3A abundance. Aim3 will characterize anti-mutagenic roles of the homologous recombination proteins BRCA1 and BRCA2 in template switch-mediated bypass of A3A-dependent abasic sites at replication forks. We will determine whether BRCA1 or BRCA2-deficiency elevates APOBEC-induced mutation in human cell lines and genetically define additional proteins involved in the pathway. Successful completion of these aims will enhance our understanding of A3A regulation and its role in cancer etiology. Additionally, these efforts will identify means to limit APOBEC-induced mutagenesis, which could provide therapeutic benefit by limiting continued tumor evolution that leads to drug resistance.


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 = $437,954 )
2026	2026	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cancer Cause and Prevention Research	000	5	1/13/2026	NON-COMPETING CONTINUATION	$437,954
														Subtotal = $437,954

Issue Date FY: 2025 ( Subtotal = $472,605 )
2025	2025	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cancer Cause and Prevention Research	000	4	1/13/2025	NON-COMPETING CONTINUATION	$425,346
2025	2025	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cancer Cause and Prevention Research	002	4	5/30/2025	NON-COMPETING CONTINUATION	$47,259
2025	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Cause and Prevention Research	001	1	2/12/2025	NEW	$0
														Subtotal = $472,605

Issue Date FY: 2024 ( Subtotal = $447,500 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cancer Cause and Prevention Research	000	3	12/29/2023	NON-COMPETING CONTINUATION	$423,947
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cancer Cause and Prevention Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$23,553
														Subtotal = $447,500

Issue Date FY: 2023 ( Subtotal = $547,907 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cancer Cause and Prevention Research	002	2	8/4/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$390,455
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Cause and Prevention Research	001	1	8/4/2023	NEW	-$314,316
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Cause and Prevention Research	000	1	2/6/2023	NEW	$471,768
														Subtotal = $547,907

Grand Total All Awards = $1,905,966

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Regulation of APOBEC3 cytidine deaminase-induced mutation during cancerdevelopment

Award Number: R01CA269784

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/06/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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