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Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection

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posted on 10.09.2019, 11:52 authored by Daniel HumphreysDaniel Humphreys
Data relating to Nature Communications Article 'Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection'

Ibler et al
Nature Communicationsvolume 10, Article number: 4040 (2019)

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 DNAdamage 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.


Methodology: The data is from a biological study use cultured human cells, which have been used in Salmonella infection experiments. The data was collected using biochemical and cell biology techniques. A full description of the methodology is provided in the file ' Ibler et al_merged manuscript'.

Funding

The cellular mechanisms underpinning the host restriction of Salmonella Typhi

Medical Research Council

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