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Molecular and Cellular Biology, October 2009, p. 5226-5237, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00894-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Saccharomyces cerevisiae Rad6 Postreplication Repair and Siz1/Srs2 Homologous Recombination-Inhibiting Pathways Process DNA Damage That Arises in asf1 Mutants{triangledown} ,{dagger}

Ellen S. Kats,1,{ddagger} Jorrit M. Enserink,1,2 Sandra Martinez,1 and Richard D. Kolodner1*

Ludwig Institute for Cancer Research, Departments of Medicine and Cellular and Molecular Medicine, and Biomedical Sciences Graduate Program, UC San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0669,1 Department of Molecular Biology, Institute of Medical Microbiology and Center of Molecular Biology and Neuroscience, University of Oslo, Rikshospitalet-Radiumhospitalet HF, N-0027 Oslo, Norway2

Received 8 July 2009/ Accepted 16 July 2009

The Asf1 and Rad6 pathways have been implicated in a number of common processes such as suppression of gross chromosomal rearrangements (GCRs), DNA repair, modification of chromatin, and proper checkpoint functions. We examined the relationship between Asf1 and different gene products implicated in postreplication repair (PRR) pathways in the suppression of GCRs, checkpoint function, sensitivity to hydroxyurea (HU) and methyl methanesulfonate (MMS), and ubiquitination of proliferating cell nuclear antigen (PCNA). We found that defects in Rad6 PRR pathway and Siz1/Srs2 homologous recombination suppression (HRS) pathway genes suppressed the increased GCR rates seen in asf1 mutants, which was independent of translesion bypass polymerases but showed an increased dependency on Dun1. Combining an asf1 deletion with different PRR mutations resulted in a synergistic increase in sensitivity to chronic HU and MMS treatment; however, these double mutants were not checkpoint defective, since they were capable of recovering from acute treatment with HU. Interestingly, we found that Asf1 and Rad6 cooperate in ubiquitination of PCNA, indicating that Rad6 and Asf1 function in parallel pathways that ubiquitinate PCNA. Our results show that ASF1 probably contributes to the maintenance of genome stability through multiple mechanisms, some of which involve the PRR and HRS pathways.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, Departments of Medicine and Cellular and Molecular Medicine, and Biomedical Sciences Graduate Program, UC San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0669. Phone: (858) 534-7804. Fax: (858) 822-4479. E-mail: rkolodner{at}ucsd.edu

{triangledown} Published ahead of print on 27 July 2009.

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

{ddagger} Present address: Office of Technology Management, UC San Francisco School of Medicine, 185 Berry Street, Suite 4603, San Francisco, CA 94107.

Molecular and Cellular Biology, October 2009, p. 5226-5237, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00894-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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