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Regulatory Mechanisms of APOBEC3B Mutagenic Activity in Cancer

Award Number: F30CA301788
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2026
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Regulatory Mechanisms of APOBEC3B Mutagenic Activity in Cancer - Regulatory Mechanisms of APOBEC3B Mutagenic Activity in Cancer PROJECT SUMMARY Mutation is an important facet of tumor development and malignant progression, driving the acquisition of hallmark cancer phenotypes such as sustained proliferative signaling and resistance to cell death. APOBEC3 (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3) enzymes are single-stranded DNA cytosine deaminases and one of the strongest drivers of mutation across human cancer. Multiple groups, including ours, have implicated APOBEC3A (A3A) and APOBEC3B (A3B) as the primary contributors of APOBEC3 mutagenesis in human cancer. Furthermore, there is growing evidence that A3A and A3B are essential drivers of drug resistance to targeted therapies in lung, prostate, and breast cancer. However, the mechanisms by which A3A and A3B become dysregulated and contribute to cancer are currently unknown. In the case of A3B, there is a wealth of evidence suggesting its mutagenic potential is regulated at the protein level through its catalytically inactive N-terminal domain (NTD). For instance, residues within the NTD govern constitutive nuclear localization, and separate NTD residues dictate interactions with RNA. Moreover, biochemical studies have shown that RNA can interfere with the DNA deamination activity of A3B. However, mechanistic role(s) for RNA in A3B biology and pathogenesis in living cells have yet to be investigated. We hypothesize that the mutagenic capacity of A3B in the nuclear compartment of living cells is negatively regulated by RNA interactions through its NTD. This idea is supported by preliminary results using a cellular A3B biosensor assay. Here, Aim 1 studies will further test this hypothesis through deep-mutation scanning to define NTD residues and structural motifs that contribute to the negative regulation of A3B in living cells. Phenotypic mutants will be further interrogated by multiple biochemical and biophysical approaches. Aim 2 will determine whether similar A3B NTD mutants occur in cancer and could be responsible for associated phenotypes including rapid adaptation, metastasis, and drug resistance. The overall impact of these studies will be a deeper mechanistic understanding of A3B in cancer, and potentially reveal a new pathway for therapeutic intervention. Training will take place at University of Texas Health San Antonio, an institution with a world-class community of DNA damage and repair researchers as well as robust core facilities. The primary goal of the training is the acquisition of skill sets that will facilitate my development into an independently funded physician-scientist, leading a laboratory that investigates the molecular drivers of somatic mutation in cancer. This includes all relevant cancer biology coursework and mentorship from senior scientists and leaders in their respective field.


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 = $40,367 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Research Manpower	000	1	4/6/2026	NEW	$40,367
														Subtotal = $40,367

Grand Total All Awards = $40,367

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Regulatory Mechanisms of APOBEC3B Mutagenic Activity in Cancer

Award Number: F30CA301788

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2026

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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