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Integrating S-phase checkpoint signaling with trans-lesion synthesis of bulky DNA adducts

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Abstract

Bulky adducts are DNA lesions generated in response to environmental agents including benzo[a]pyrene (a combustion product) and solar ultraviolet radiation. Error-prone replication of adducted DNA can cause mutations, which may result in cancer. To minimize the detrimental effects of bulky adducts and other DNA lesions, S-phase checkpoint mechanisms sense DNA damage and integrate DNA repair with ongoing DNA replication. The essential protein kinase Chk1 mediates the S-phase checkpoint, inhibiting initiation of new DNA synthesis and promoting stabilization and recovery of stalled replication forks. Here we review the mechanisms by which Chk1 is activated in response to bulky adducts and potential mechanisms by which Chk1 signaling inhibits the initiation stage of DNA synthesis. Additionally, we discuss mechanisms by which Chk1 signaling facilitates bypass of bulky lesions by specialized Y-family DNA polymerases, thereby attenuating checkpoint signaling and allowing resumption of normal cell cycle progression.

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Acknowledgments

Cited work from the authors’ laboratories was supported by NIH grant ES09558 to C.V. and by grants (17013041 and 16370077) from the Japanese Ministry of Education, Culture, Sports, Science and Technology to H.O.

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  1. Department of Genetics and Genomics, Boston University School of Medicine, 715 Albany Street, Boston, MA, 02118, USA

    Laura R. Barkley & Cyrus Vaziri

  2. Institute for Virus Research, Kyoto University, 53 Shogoin-Kawaracho, Sakyo-ku, Kyoto, 606-8507, Japan

    Haruo Ohmori

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  1. Laura R. Barkley
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Correspondence to Cyrus Vaziri.

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Barkley, L.R., Ohmori, H. & Vaziri, C. Integrating S-phase checkpoint signaling with trans-lesion synthesis of bulky DNA adducts. Cell Biochem Biophys 47, 392–408 (2007). https://doi.org/10.1007/s12013-007-0032-7

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