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Molecular and Cellular Biology, November 2000, p. 8283-8289, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

DNA Replication Is Required To Elicit Cellular Responses to Psoralen-Induced DNA Interstrand Cross-Links

Yassmine M. N. Akkari,* Raynard L. Bateman, Carol A. Reifsteck, Susan B. Olson, and Markus Grompe

Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, Oregon 97201

Received 24 November 1999/Returned for modification 7 February 2000/Accepted 21 July 2000

Following introduction of DNA interstrand cross-links (ICLs), mammalian cells display chromosome breakage or cell cycle delay with a 4N DNA content. To further understand the nature of the delay, previously described as a G2/M arrest, we developed a protocol to generate ICLs during specific intervals of the cell cycle. Synchronous populations of G1, S, and G2 cells were treated with photoactivated 4'-hydroxymethyl-4,5',8-trimethylpsoralen (HMT) and scored for normal passage into mitosis. In contrast to what was found for ionizing radiation, ICLs introduced during G2 did not result in a G2/M arrest, mitotic arrest, or chromosome breakage. Rather, subsequent passage through S phase was required to trigger both chromosome breakage and arrest in the next cell cycle. Similarly, ICLs introduced during G1 did not cause a G1/S arrest. We conclude that DNA replication is required to elicit the cellular responses of cell cycle arrest and genomic instability after psoralen-induced ICLs. In primary human fibroblasts, the 4N DNA content cell cycle arrest triggered by ICLs was long lasting but reversible. Kinetic analysis suggested that these cells could remove up to ~2,500 ICLs/genome at an average rate of 11 ICLs/genome/h.

* Corresponding author. Mailing address: Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., L103, Portland, OR 97201. Phone: (503) 494-6206. Fax: (503) 494-6886. E-mail: akkariy{at}ohsu.edu.

Molecular and Cellular Biology, November 2000, p. 8283-8289, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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