Cutting edge: Chk1 directs senescence and mitotic catastrophe in recovery from G(2) checkpoint arrest.
Résumé
Abstract Besides the well understood DNA damage response via establishment of G(2) checkpoint arrest, novel studies focus on the recovery from arrest by checkpoint override to monitor cell cycle re-entry. The aim of this study was to investigate the role of Chk1 in the recovery from G(2) checkpoint arrest in HCT116 wt, p53(-/-), and p21(-/-) colorectal cancer cell lines following H(2)O(2) treatment. Firstly, DNA damage caused G(2) checkpoint activation via Chk1. Secondly, overriding G(2) checkpoint led to (i) mitotic slippage, cell cycle re-entry in G(1), and subsequent G(1) arrest associated with senescence or (ii) premature mitotic entry in the absence of p53/p21(WAF1) causing mitotic catastrophe. We revealed subtle differences in the initial Chk1-involved G(2) arrest with respect to p53/p21(WAF1): absence of either protein led to late G(2) arrest instead of the classic G(2) arrest during checkpoint initiation, and this impacted on the release back into the cell cycle. Thus, G(2) arrest correlated with downstream senescence, but late G(2) arrest led to mitotic catastrophe, while both cell cycle re-entries were linked to upstream Chk1 signaling. Chk1 knockdown deciphered that Chk1 defines long-term DNA damage responses causing cell cycle re-entry. We propose that recovery from oxidative DNA damage-induced G(2) arrest requires Chk1. It works as cutting edge and navigates cells to senescence or mitotic catastrophe. The decision, however, seems to depend on p53/p21(WAF1). The general relevance of Chk1 as an important determinant of recovery from G(2) checkpoint arrest was verified in HT29 colorectal cancer cells.