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

Nat Commun.. 2019; 
Ibler AEM1,2, ElGhazaly M1, Naylor KL1, Bulgakova NA1, F El-Khamisy S3,4, Humphreys D5.
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Catalog Antibody RPA32- pS33/pRPA32/1:1000, A300-246A), Sigma (FLAG M2 diluted 1:1000, F3165), GenScript (Myc diluted 1:1000, A00172-200), Qiagen (His diluted 1:1000, 34660), Millipore (yH2AX diluted 1:1000, 05-636-I), Novusbio (53BP1 diluted 1:1000, NB100-304), BD Bioscience (BrdU diluted 1:200, 347580) Get A Quote

摘要

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 mechanism... More

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