Date of Award

Fall 11-21-2025

Embargo Period

11-26-2025

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

Additional Department

Biomedical Sciences

College

College of Graduate Studies

First Advisor

Philip H. Howe

Second Advisor

David T. Long

Third Advisor

Sophie Paczesny

Fourth Advisor

Aguirre De Cubas

Fifth Advisor

Vamsi Gangaraju

Abstract

Nucleic acid sensing pathways are key mediators of innate immune surveillance and antitumor defense. Among these, the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway plays a central role by detecting cytosolic double-stranded DNA (dsDNA) and inducing the production of type I interferons (IFNs) and interferon-stimulated genes (ISGs), thereby promoting immune cell recruitment and tumor immunogenicity.

This dissertation investigates the role of a nucleic acid binding protein, Poly(rC) Binding Protein 1 (PCBP1), as a tumor suppressor that activates the cGAS-STING pathway and impairs breast cancer development. Previous studies have shown that PCBP1 is downregulated in several cancer types and metastatic lesions. Here, we show that high PCBP1 expression is associated with improved survival in breast cancer patients. Using a transgenic mouse model of mammary tumorigenesis with conditional PCBP1 knockout in mammary epithelial cells, animals expressing PCBP1 exhibited significantly reduced tumor burden, together with increased type I IFN signaling and chemokine expression associated with enhanced cytotoxic T cell infiltration compared to knockout animals.

Mechanistically, PCBP1 functions as a nucleic acid co-sensor that binds DNA containing single-stranded poly-cytosine tracts through its KH domains, thereby increasing cGAS affinity for these DNA substrates without altering its intrinsic catalytic activity. This interaction enhances 2′3′-cyclic GMP–AMP (2’3’-cGAMP) synthesis and downstream STING activation, leading to amplified IFN and ISG responses in both mouse and human mammary epithelial cells. Importantly, mutation of PCBP1’s conserved GXXG loops within its KH domains abolished nucleic acid binding and cGAS activation, confirming the structural basis of its co-sensing function.

On a clinical level, reduced PCBP1 expression may contribute to poor responsiveness to immune checkpoint blockade due to diminished tumor immunogenicity. Therapeutic approaches aiming at stabilizing PCBP1 or combining STING agonists with immune checkpoint inhibitors may therefore enhance antitumor immunity in PCBP1-deficient cancers.

Rights

Copyright is held by the author. All rights reserved.

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