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Vol. 16, Issue 5, 2372-2381, May 2005
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Department of Biochemistry, Vanderbilt University, Nashville, TN 37232
Submitted November 17, 2004;
Revised February 1, 2005;
Accepted February 19, 2005
Monitoring Editor: John Cleveland
ATR associates with the regulatory protein ATRIP that has been proposed to localize ATR to sites of DNA damage through an interaction with single-stranded DNA (ssDNA) coated with replication protein A (RPA). We tested this hypothesis and found that ATRIP is required for ATR accumulation at intranuclear foci induced by DNA damage. A domain at the N terminus of ATRIP is necessary and sufficient for interaction with RPA–ssDNA. Deletion of the ssDNA–RPA interaction domain of ATRIP greatly diminished accumulation of ATRIP into foci. However, the ATRIP–RPA–ssDNA interaction is not sufficient for ATRIP recognition of DNA damage. A splice variant of ATRIP that cannot bind to ATR revealed that ATR association is also essential for proper ATRIP localization. Furthermore, the ATRIP–RPA–ssDNA interaction is not absolutely essential for ATR activation because ATR phosphorylates Chk1 in cells expressing only a mutant of ATRIP that does not bind to RPA–ssDNA. These data suggest that binding to RPA–ssDNA is not the essential function of ATRIP in ATR-dependent checkpoint signaling and ATR has an important function in properly localizing the ATR–ATRIP complex.
Abbreviations used: ATM, ataxia-telangiectasia mutated; ATR, ATM and Rad3 related; HU, hydroxyurea; IR, ionizing radiation; NLS, nuclear localization signal; RPA, replication protein A; ssDNA, single-stranded DNA.
Address correspondence to: David Cortez (david.cortez{at}vanderbilt.edu).
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