Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2.
Using chemical genetics to reversibly inhibit Cdk1, we find that cells arrested in late G2 are unable to delay mitotic entry after irradiation. Late G2 cells detect DNA damage lesions and form gamma-H2AX foci but fail to activate Chk1. This reflects a lack of DNA double-strand break processing because late G2 cells fail to recruit RPA (replication protein A), ATR (ataxia telangiectasia and Rad3 related), Rad51, or CtIP (C-terminal interacting protein) to sites of radiation-induced damage, events essential for both checkpoint activation and initiation of DNA repair by homologous recombination. Remarkably, inhibition of Akt/PKB (protein kinase B) restores DNA damage processing and Chk1 activation after irradiation in late G2. These data demonstrate a previously unrecognized role for Akt in cell cycle regulation of DNA repair and checkpoint activation. Because Akt/PKB is frequently activated in many tumor types, these findings have important implications for the evolution and therapy of such cancers.
Xu
Naihan
N
The Beatson Institute for Cancer Research, Glasgow G61 1BD, Scotland, UK.
Hegarat
Nadia
N
Black
Elizabeth J
EJ
Scott
Mary T
MT
Hochegger
Helfrid
H
Gillespie
David A
DA
D000818:Animals; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1; D002645:Chickens; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D016195:G2 Phase; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D013329:Structure-Activity Relationship
C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D009025:Morpholines; D011753:Pyrones; D004247:DNA; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D051057:Proto-Oncogene Proteins c-akt