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A novel DNA damage response to replicative stress

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.

Ibler A, Bulgakova N, El-Khamisy SF, Humphreys D (2019). A novel DNA damage response to replicative stress by the typhoid toxin facilitates cellular senescence and Salmonella infection. Nature communications, 10: 4040

Professor of Molecular Medicine, Director of Research and Innovation and co-founder of the Healthy Life Span Institute, University of Sheffield, United Kingdom

Sherif El-Khamisy is a Wellcome Trust Investigator and co-founder of the Healthy Lifespan Institute at the University of Sheffield. El-Khamisy lab studies how cells maintain genomic integrity and their impact on health. The lab uses interdisciplinary approach fusing genetics, chemistry and biology with clinical expertise. We use mouse and zebrafish models to stay ageing and multimorbidity at the molecular and organismal level. We link our molecular understanding to public health challenges through interactions with social scientists.