# Cellular transcriptomics of arrested normal lung fibroblasts IMR-90 infected with Human Adenovirus 5 E1A mutants

## TL;DR

This study investigates how a modified E1A protein from human adenovirus can still push infected lung cells into S-phase despite losing key interactions, using transcriptomic analysis.

## Contribution

The study reveals a novel E1A mutant that induces S-phase without canonical interactions and identifies MYC upregulation as a potential mechanism.

## Key findings

- The E1A289Rdl2–11/YC mutant drives S-phase induction despite losing E2F/DP and retinoblastoma protein binding.
- MYC mRNA is significantly upregulated by the mutant compared to other viruses.
- The mutant fails to suppress the innate immune response due to loss of p300/CBP binding.

## Abstract

Induction of S-phase is paramount to the replication of most human DNA viruses. Human adenoviruses have evolved sophisticated mechanisms that drive the infected cells into S-phase to ensure that viral genomes are efficiently replicated. We have identified an E1A mutant, E1A289Rdl2–11/YC, that disrupts the canonical means of S-phase induction by E1A. Specifically, this mutant abrogates binding of E1A to the E2F/DP complex as well as to the retinoblastoma protein. Yet, we show that this mutant can still effectively drive the infected cell into S-phase. We explore potential mechanisms of how this occurs via cellular transcriptomic analysis 16 hours after infection. We show that this mutant induces many cell-cycle specific genes to drive S-phase. Interestingly, MYC mRNA is significantly upregulated by this mutant as compared to other viruses investigated. This MYC upregulation, together with normal expression of E4orf6/7 in this mutant, may contribute to efficient S-phase induction. We also demonstrate that this mutant is unable to effectively suppress innate immune response to infection, likely due to loss of p300/CBP binding caused by deletion of E1A residues 2 to 11.