Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-12064-1
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Funding
- Medical Research Council SHIMA [MR/K015753/1]
- Royal Society
- University of Sheffield
- Medical Research Council New Investigator Research Grant [MR/M011771/2]
- British Infection Association Fellowship [BIA-2018/FEL/AI]
- Wellcome Trust [215485/Z/19/Z]
- Lister Institute of Preventative Medicine Fellowship
- MRC [MR/M011771/1, MR/M011771/2] Funding Source: UKRI
- UKRI [MR/S034390/1] Funding Source: UKRI
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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 (gamma H2AX) 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 gamma H2AX 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.
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