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.
Highlights
Damage to our genomes, arising endogenously during DNA replication, or exogenously from genotoxins, often generates DNA breaks causing mutations and chromosomal aberrations, which underlie diseases[1]
Discussion γH2AX is a central hub in the DNA damage response (DDR) that orchestrates DNA repair and cell fate
We report a non-canonical DDR response characterised by signature accumulation of γH2AX at the nuclear periphery—the RING phenotype—generated via ATR at heterochromatin
Summary
Damage to our genomes, arising endogenously during DNA replication, or exogenously from genotoxins, often generates DNA breaks causing mutations and chromosomal aberrations, which underlie diseases[1]. The ATR pathway pauses the cell cycle, halts firing of DNA replication at new sites and stabilises forks for repair This is key as persistent replication stress converts forks into DSBs, the most lethal form of damage that is counteracted by the ATM pathway[1,5]. Given the importance of the DDR in coordinating diverse cellular processes, it is perhaps not surprising that pathogenic bacteria have evolved sophisticated ways to manipulate the host DDR to execute virulence strategies and establish infections[11]. This is exemplified by genotoxic strains of Salmonella[12,13,14,15,16], the human-adapted intracellular pathogen Salmonella. The mechanisms by which the two disease manifestations, typhoid fever and chronic carriage, are mediated remain unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
