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Molecular and Cellular Biology, December 2002, p. 8552-8561, Vol. 22, No. 24
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.24.8552-8561.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

An ATR- and Chk1-Dependent S Checkpoint Inhibits Replicon Initiation following UVC-Induced DNA Damage

Timothy P. Heffernan,1 Dennis A. Simpson,1 Alexandra R. Frank,1 Alexandra N. Heinloth,2 Richard S. Paules,2 Marila Cordeiro-Stone,1 and William K. Kaufmann1*

Department of Pathology and Laboratory Medicine, Center for Environmental Health and Susceptibility, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599,1 Growth Control and Cancer Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 277092

Received 20 June 2002/ Returned for modification 12 July 2002/ Accepted 10 September 2002

Inhibition of replicon initiation is a stereotypic DNA damage response mediated through S checkpoint mechanisms not yet fully understood. Studies were undertaken to elucidate the function of checkpoint proteins in the inhibition of replicon initiation following irradiation with 254 nm UV light (UVC) of diploid human fibroblasts immortalized by the ectopic expression of telomerase. Velocity sedimentation analysis of nascent DNA molecules revealed a 50% inhibition of replicon initiation when normal human fibroblasts were treated with a low dose of UVC (1 J/m2). Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and AT-like disorder fibroblasts, which lack an S checkpoint response when exposed to ionizing radiation, responded normally when exposed to UVC and inhibited replicon initiation. Pretreatment of normal and AT fibroblasts with caffeine or UCN-01, inhibitors of ATR (AT mutated and Rad3 related) and Chk1, respectively, abolished the S checkpoint response to UVC. Moreover, overexpression of kinase-inactive ATR in U2OS cells severely attenuated UVC-induced Chk1 phosphorylation and reversed the UVC-induced inhibition of replicon initiation, as did overexpression of kinase-inactive Chk1. Taken together, these data suggest that the UVC-induced S checkpoint response of inhibition of replicon initiation is mediated by ATR signaling through Chk-1 and is independent of ATM, Nbs1, and Mre11.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, CB 7295, University of North Carolina, Chapel Hill, NC 27599-7295. Phone: (919) 966-8209. Fax: (919) 966-9673. E-mail: bill_kaufmann{at}med.unc.edu.

Molecular and Cellular Biology, December 2002, p. 8552-8561, Vol. 22, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.24.8552-8561.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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