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Molecular and Cellular Biology, June 2009, p. 3113-3123, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.00071-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Separate Domains of Rev1 Mediate Two Modes of DNA Damage Bypass in Mammalian Cells{triangledown} ,{dagger}

Jacob G. Jansen,1,{ddagger} Anastasia Tsaalbi-Shtylik,1,{ddagger} Giel Hendriks,1 Himabindu Gali,2 Ayal Hendel,3 Fredrik Johansson,4 Klaus Erixon,4,5 Zvi Livneh,3 Leon H. F. Mullenders,1 Lajos Haracska,2 and Niels de Wind1*

Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands,1 Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvari korut 62, H-6726 Szeged, Hungary,2 Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel,3 Stockholm University, Department of Genetics, Microbiology and Toxicology, Svante Arrhenius väg 16, 10691 Stockholm, Sweden,4 Erixon Scientific Consulting, Stockholm, Sweden5

Received 16 January 2009/ Returned for modification 11 February 2009/ Accepted 20 March 2009

The Y family DNA polymerase Rev1 has been proposed to play a regulatory role in the replication of damaged templates. To elucidate the mechanism by which Rev1 promotes DNA damage bypass, we have analyzed the progression of replication on UV light-damaged DNA in mouse embryonic fibroblasts that contain a defined deletion in the N-terminal BRCT domain of Rev1 or that are deficient for Rev1. We provide evidence that Rev1 plays a coordinating role in two modes of DNA damage bypass, i.e., an early and a late pathway. The cells carrying the deletion in the BRCT domain are deficient for the early pathway, reflecting a role of the BRCT domain of Rev1 in mutagenic translesion synthesis. Rev1-deficient cells display a defect in both modes of DNA damage bypass. Despite the persistent defect in the late replicational bypass of fork-blocking (6-4)pyrimidine-pyrimidone photoproducts, overall replication is not strongly affected by Rev1 deficiency. This results in almost completely replicated templates that contain gaps encompassing the photoproducts. These gaps are inducers of DNA damage signaling leading to an irreversible G2 arrest. Our results corroborate a model in which Rev1-mediated DNA damage bypass at postreplicative gaps quenches irreversible DNA damage responses.

* Corresponding author. Mailing address: Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31 715269627. Fax: 31 715268284. E-mail: n.de_wind{at}lumc.nl

{triangledown} Published ahead of print on 30 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} J.G.J. and A.T.-S. contributed equally to this work.

Molecular and Cellular Biology, June 2009, p. 3113-3123, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.00071-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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