Cutting edge: Chk1 directs senescence and mitotic catastrophe in recovery from G₂ checkpoint arrest.
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 (human colorectal cancer) wt, p53(-/-) and p21(-/-) 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 the release back into the cell cycle. Thus, G(2) arrest correlated with downstream senescence, but late G(2) arrest led to mitotic catastrophe, although both cell cycle re-entries were linked to upstream Chk1 signalling. 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.
Poehlmann
Angela
A
Department of Pathology, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, Magdeburg, Germany. Angela.Poehlmann@med.ovgu.de
Habold
Caroline
C
Walluscheck
Diana
D
Reissig
Kathrin
K
Bajbouj
Khuloud
K
Ullrich
Oliver
O
Hartig
Roland
R
Gali-Muhtasib
Hala
H
Diestel
Antje
A
Roessner
Albert
A
Schneider-Stock
Regine
R
D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D016195:G2 Phase / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016877:Oxidants; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1