# A novel role for the E2F transcription factor and the ER stress sensor IRE1 in cytoplasmic DNA accumulation

## TL;DR

This study reveals how E2F and IRE1 work together to prevent DNA buildup in exocrine tissues like the salivary gland.

## Contribution

The study uncovers a novel role for E2F and IRE1 in cytoplasmic DNA accumulation and ER homeostasis in exocrine tissues.

## Key findings

- Loss of de2f1b causes DNA damage and cytoplasmic DNA accumulation in Drosophila salivary glands.
- IRE1 is essential for ER homeostasis and preventing cytoDNA accumulation in exocrine tissues.
- IRE1 activity is reduced in de2f1b-deficient glands, leading to ER dysfunction and cytoDNA buildup.

## Abstract

The E2F family of transcription factors are key regulators of the cell cycle in all metazoans. While they are primarily known for their role in cell cycle progression, E2Fs also play broader roles in cellular physiology, including the maintenance of exocrine tissue homeostasis. However, the underlying mechanisms that render exocrine cells particularly sensitive to E2F deregulation remain poorly understood. The Drosophila larval salivary gland, like its mammalian counterpart, is an exocrine tissue that produces large quantities of “glue proteins” in the endoplasmic reticulum. Here, we show that E2F activity is important for the exocrine function of the Drosophila salivary gland. The loss of de2f1b, an alternatively spliced isoform of Drosophila E2F1, leads to elevated DNA damage and accumulation of cytoplasmic DNA (cytoDNA) in the salivary glands. Surprisingly, we found that IRE1, a key sensor of the unfolded protein response, is required for endoplasmic reticulum homeostasis during development that is critical for preventing cytoDNA accumulation in the salivary gland. Importantly, we found evidence demonstrating that IRE1 activity is attenuated in de2f1b-deficient salivary glands, contributing to endoplasmic reticulum dysfunction and cytoDNA accumulation. Together, these findings reveal an unanticipated link between endoplasmic reticulum homeostasis and cytoDNA processing and offer mechanistic insights into why exocrine tissues are particularly vulnerable to E2F deregulation.