Abstract
DNA damage response is crucially involved in cellular senescence. We have previously shown that excess thymidine, which stalls DNA replication forks, induces cellular senescence in human cells, and ERK1/2 play a key role in the induction of it. In this study, we found that Chk1 and ERK1/2 were activated to promote cell survival upon addition of excess thymidine. Knockdown of ERK1/2 activated Chk1, and conversely, knockdown of Chk1 activated ERK1/2, which observations suggested a mechanism for compensatory activation of Chk1 and ERK1/2 in the absence of ERK1/2 and Chk1, respectively. We also found that Chk1 functioned mainly at the onset of cellular senescence, and on the other hand, ERK1/2 functioned for a more extended period to induce cellular senescence. Our findings suggested that Chk1 and ERK1/2 were activated to promote cell survival upon addition of excess thymidine, but prolonged activation of ERK1/2 led to cellular senescence. This implies a pleiotropic effect of ERK1/2 in cellular senescence induced by excess thymidine.