Typhoid Toxin Exhausts the RPA Response to DNA Replication Stress Driving Senescence and Salmonella Infection

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Sep 8

PMID 31492859

Citations 32

Authors

Angela E M Ibler

Mohamed ElGhazaly

Kathryn L Naylor

Natalia A Bulgakova

Sherif F El-Khamisy

Daniel Humphreys

Affiliations

Soon will be listed here.

Abstract

Salmonella Typhi activates the host DNA damage response through the typhoid toxin, facilitating typhoid symptoms and chronic infections. Here we reveal a non-canonical DNA damage response, which we call RING (response induced by a genotoxin), characterized by accumulation of phosphorylated histone H2AX (γH2AX) at the nuclear periphery. RING is the result of persistent DNA damage mediated by toxin nuclease activity and is characterized by hyperphosphorylation of RPA, a sensor of single-stranded DNA (ssDNA) and DNA replication stress. The toxin overloads the RPA pathway with ssDNA substrate, causing RPA exhaustion and senescence. Senescence is also induced by canonical γΗ2ΑΧ foci revealing distinct mechanisms. Senescence is transmitted to non-intoxicated bystander cells by an unidentified senescence-associated secreted factor that enhances Salmonella infections. Thus, our work uncovers a mechanism by which genotoxic Salmonella exhausts the RPA response by inducing ssDNA formation, driving host cell senescence and facilitating infection.

Citing Articles

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