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S‐sulfhydration of MEK1 leads to PARP‐1 activation and DNA damage repair

The repair of DNA damage is fundamental to normal cell development and replication. Hydrogen sulfide (H2S) is a novel gasotransmitter that has been reported to protect cellular aging. Here, we show that H2S attenuates DNA damage in human endothelial cells and fibroblasts by S‐sulfhydrating MEK1 at cysteine 341, which leads to PARP‐1 activation. H2S‐induced MEK1 S‐sulfhydration facilitates the translocation of phosphorylated ERK1/2 into nucleus, where it activates PARP‐1 through direct interaction. Mutation of MEK1 cysteine 341 inhibits ERK phosphorylation and PARP‐1 activation. In the presence of H2S, activated PARP‐1 recruits XRCC1 and DNA ligase III to DNA breaks to mediate DNA damage repair, and cells are protected from senescence.