# PCBP1 binding to single-stranded poly-cytosine motifs enhances cGAS sensing and impairs breast cancer development

## TL;DR

PCBP1 enhances immune sensing in breast cancer by binding to specific DNA sequences, improving tumor control and survival.

## Contribution

PCBP1 is identified as a sequence-specific co-sensor that amplifies cGAS-STING signaling in breast cancer.

## Key findings

- PCBP1 expression correlates with improved survival and reduced tumor burden in breast cancer.
- PCBP1 binds cytosine-rich motifs and increases cGAS affinity for nucleic acids.
- Mutation of PCBP1's GXXG loops impairs its function and cGAS activation.

## Abstract

The cGAS-STING pathway plays a central role in controlling tumor progression through nucleic acid sensing and type I Interferon production. Here, we identify Poly(rC) Binding Protein 1 as a tumor suppressor that amplifies cGAS-STING signaling in breast cancer. Using patient datasets and a transgenic mouse model with conditional PCBP1 knockout in mammary epithelial cells, we show that PCBP1 expression correlates with improved survival, reduced tumor burden, increased type I Interferon and Interferon Stimulated Gene expression, and elevated cytotoxic T cell infiltration. Mechanistically, PCBP1 binds cytosine-rich single-stranded motifs via its KH domains and increases cGAS affinity to these nucleic acids. Mutation of PCBP1’s conserved GXXG loops impairs nucleic acid binding and cGAS activation. Although cGAS is a double-stranded DNA sensor with no intrinsic sequence specificity, we uncover that the single-stranded nucleic-acid binding protein PCBP1 enhances cGAS sensing by engaging sequence-specific motifs, acting as a nucleic acid co-sensor that impairs tumorigenesis.

Sequence-specific binding of PCBP1 to poly-cytosine DNA enhances cGAS-STING activation and interferon-driven immune responses, revealing a new co-sensing mechanism that restrains breast tumor growth.