DNA replication stress-induced phosphorylation of cyclic AMP response element-binding protein mediated by ATM

doi:10.1074/jbc.M509577200

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Papers In Press, published online ahead of print November 17, 2005
J. Biol. Chem, 10.1074/jbc.M509577200
Submitted on August 31, 2005
Revised on November 16, 2005
Accepted on November 16, 2005

DNA replication stress-induced phosphorylation of cyclic AMP response element-binding protein mediated by ATM

Gerald E. Dodson and Randal S. Tibbetts

Pharmacology, University of Wisconsin, Madison, WI 53706

Corresponding Author: rstibbetts{at}wisc.edu

The DNA damage response-regulators ATM (ataxia-telangiectasia-mutated) and ATR (ATM-Rad3-related) are structurally and functionally related protein kinases that exhibit nearly identical substrate specificities in vitro. Current paradigms hold that the relative contributions of ATM and ATR to nuclear substrate phosphorylation are dictated by the type of initiating DNA lesion; ATM-dependent substrate phosphorylation is principally activated by DNA double-strand breaks (DSBs), whereas ATR-dependent substrate phosphorylation is induced by UV light and other forms of DNA replication stress. In this report we employed the cyclic AMP response element-binding protein to provide evidence for substrate discrimination by ATM and ATR in cellulo. ATM and ATR phosphorylate CREB in vitro and CREB is phosphorylated on Ser-121 in intact cells in response to ionizing radiation (IR), UV light, and hydroxyurea (HU). The UV- and HU-induced phosphorylation of CREB was delayed in comparison to the canonical ATR substrate, CHK1, suggesting potentially different mechanisms of phosphorylation. UV-induced CREB phosphorylation temporally correlated with ATM autophosphorylation on Ser-1981 and an ATM-specific siRNA suppressed CREB phosphorylation in response to this stimulus. UV-induced CREB phosphorylation was absent in ATM-deficient cells, confirming that ATM is required for CREB phosphorylation in UV-damaged cells. Interestingly, RNAi-mediated suppression of ATR partially inhibited CREB phosphorylation in response to UV, which correlated with reduced phosphorylation of ATM on Ser-1981. These findings suggest that ATM is the major genotoxin-induced CREB kinase in mammalian cells and that ATR lies upstream of ATM in a UV-induced signaling pathway.

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