Estrogen inhibits ATR signaling to cell cycle checkpoints and DNA repair.
DNA damage activates the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase signal cascade. How this system is restrained is not understood. We find that in estrogen receptor (ER)-positive breast cancer cells, UV or ionizing radiation and hydroxyurea rapidly activate ATR-dependent phosphorylation of endogenous p53 and Chk1. 17-beta-estradiol (E(2)) substantially blocks ATR activity via plasma membrane-localized ERalpha. E(2)/ER reduces the enhanced association of ATR andTopBP1 proteins that follows DNA damage and strongly correlates to ATR activity. E(2) inhibits ATR activation through rapid PI3K/AKT signaling: AKT phosphorylates TopBP1 at Serine 1159, thereby preventing the enhanced association of ATR with TopBP1 after DNA damage. E(2) also inhibits Claspin:Chk1 protein association via AKT phosphorylation of Chk1, preventing Chk1 signaling to the G2/M checkpoint. ATR-phosphorylation of p53 induces p21 transcription, prevented by E(2)/ER. E(2) delays the assembly and prolongs the resolution of gammaH2AX and Rad51 nuclear foci and delays DNA repair. E(2)/ER also increases the chromosomal damage seen from cell exposure to IR. Therefore, the restraint of ATR cascade activation may be a novel estrogen action relevant to breast cancer.
Pedram
Ali
A
Department of Medicine, University of California, Irvine, Irvine CA 92717, USA.
Razandi
Mahnaz
M
Evinger
Albert J
AJ
Lee
Eva
E
Levin
Ellis R
ER
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004260:DNA Repair / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013379:Substrate Specificity / Q000187:drug effects
D018797:Cell Cycle Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047428:Protein Kinase Inhibitors; D004958:Estradiol; D011494:Protein Kinases; C576897:Atr protein, mouse; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt