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  • Original Paper
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Induction of a caffeine-sensitive S-phase cell cycle checkpoint by psoralen plus ultraviolet A radiation

Oncogene volume 22, pages 6119–6128 (2003)Cite this article

An Erratum to this article was published on 03 February 2005

Abstract

Induction of interstrand crosslinks (ICLs) in chromosomal DNA is considered a major reason for the antiproliferative effect of psoralen plus ultraviolet A (PUVA). It is unclear as to whether PUVA-induced cell cycle arrest is caused by ICLs mechanically stalling replication forks or by triggering cell cycle checkpoints. Cell cycle checkpoints serve to maintain genomic stability by halting cell cycle progression to prevent replication of damaged DNA templates or segregation of broken chromosomes. Here, we show that HaCaT keratinocytes treated with PUVA arrest with S-phase DNA content. Cells that had completed DNA replication were not perturbed by PUVA and passed through mitosis. Cells treated with PUVA during G1-phase continued traversing G1 until arresting in early S-phase. PUVA induced rapid phosphorylation of the Chk1 checkpoint kinase at Ser345 and a concomitant decrease in Cdc25A levels. Chk1 phosphorylation, decrease of Cdc25 A levels and S-phase arrest were abolished by caffeine, demonstrating that active checkpoint signaling rather than passive mechanical blockage by ICLs causes the PUVA-induced replication arrest. Overexpression of Cdc25A only partially overrode the S-phase arrest, suggesting that additional signaling events implement PUVA-induced S-phase arrest.

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Abbreviations

UVA:

ultraviolet A

ICLs:

interstrand crosslinks

PUVA:

psoralen plus ultraviolet A

MOP:

8-methoxy-psoralen

PBS:

phosphate-buffered saline

BrdU:

bromo-deoxy-uridine

PI:

propidium iodide

HU:

hydroxyurea

RDS:

radio-resistant DNA synthesis.

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Acknowledgements

We thank L Hengst. B Lüscher. J Lukas and DA Wolf for insightful discussions and technical advice, and I Hoffmann and N Fusenig for providing cell lines. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (He2518/2-1).

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  1. Klinik und Poliklinik für Dermatologie und Allergologie, Ludwig-Maximilians-University, Frauenlobstr. 9-11, Munich, D-80337, Germany

    Christoph Joerges, Inge Kuntze & Thomas Herzinge

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  1. Christoph Joerges
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  2. Inge Kuntze
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  3. Thomas Herzinge
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Correspondence to Thomas Herzinge.

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Joerges, C., Kuntze, I. & Herzinge, T. Induction of a caffeine-sensitive S-phase cell cycle checkpoint by psoralen plus ultraviolet A radiation. Oncogene 22, 6119–6128 (2003). https://doi.org/10.1038/sj.onc.1206613

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