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Originally published as MBoC in Press, 10.1091/mbc.E09-01-0085 on May 28, 2009

Vol. 20, Issue 14, 3374-3389, July 15, 2009

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Estrogen Inhibits ATR Signaling to Cell Cycle Checkpoints and DNA Repair

Ali Pedram*, Mahnaz Razandi*,{dagger}, Albert J. Evinger*, Eva Lee*, and Ellis R. Levin*,{dagger},{ddagger}

{dagger}Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, Long Beach, CA 90822; Departments of *Medicine and {ddagger}Biochemistry, University of California, Irvine, Irvine CA 92717

Submitted January 28, 2009; Revised April 21, 2009; Accepted May 18, 2009
Monitoring Editor: John L. Cleveland

InCytes from MBC

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-β-estradiol (E2) substantially blocks ATR activity via plasma membrane-localized ER{alpha}. E2/ER reduces the enhanced association of ATR andTopBP1 proteins that follows DNA damage and strongly correlates to ATR activity. E2 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. E2 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 E2/ER. E2 delays the assembly and prolongs the resolution of {gamma}H2AX and Rad51 nuclear foci and delays DNA repair. E2/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.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E09-01-0085) on May 28, 2009.

Address correspondence to: Ellis R. Levin (ellis.levin{at}med.va.gov)

Abbreviations used: ATR, ataxia telangiectasia-mutated and Rad3-related; ATM, ataxia telangiectasia-mutated; Chk1, checkpoint kinase1; Cdk1, cyclin-dependent kinae 1; DPN, diarylpropionitrile; UV, ultraviolet; EGF, epidermal growth factor; ER, estrogen receptor; IR, ionizing radiation; HU, hydroxyurea; PPT, propyl-pyrazole-triol.


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