Nucleic Acids Research Advance Access originally published online on March 5, 2009
Nucleic Acids Research 2009 37(8):2549-2559; doi:10.1093/nar/gkp105
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Nucleic Acids Research, 2009, Vol. 37, No. 8 2549-2559
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Genome Integrity, Repair and Replication |
PCNA monoubiquitylation and DNA polymerase 
ubiquitin-binding domain are required to prevent 8-oxoguanine-induced mutagenesis in Saccharomyces cerevisiae
1CEA, iRCM, UMR217 CNRS ‘Radiobiologie Moléculaire et Cellulaire’, 18 route du Panorama, BP6, 92265-Fontenay aux Roses, France, 2LDMH-‘Universidade Federal do Rio de Janeiro’-UFRJ, CCS Faculdade de Farmácia. CEP: 21941-970 Rio de Janeiro, Brazil and 3Cancer Research UK, London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms EN6 3LD, UK
*To whom correspondence should be addressed. Tel: +33 1 46 54 88 58; Fax: +33 1 46 54 88 59; Email: serge.boiteux{at}cea.fr
Received December 6, 2008. Revised January 5, 2009. Accepted February 8, 2009.
7,8-Dihydro-8-oxoguanine (8-oxoG) is an abundant and mutagenic DNA lesion. In Saccharomyces cerevisiae, the 8-oxoG DNA N-glycosylase (Ogg1) acts as the primary defense against 8-oxoG. Here, we present evidence for cooperation between Rad18–Rad6-dependent monoubiquitylation of PCNA at K164, the damage-tolerant DNA polymerase 
and the mismatch repair system (MMR) to prevent 8-oxoG-induced mutagenesis. Preventing PCNA modification at lysine 164 (pol30-K164R) results in a dramatic increase in GC to TA mutations due to endogenous 8-oxoG in Ogg1-deficient cells. In contrast, deletion of RAD5 or SIZ1 has little effect implying that the modification of PCNA relevant for preventing 8-oxoG-induced mutagenesis is monoubiquitin as opposed to polyubiquitin or SUMO. We also report that the ubiquitin-binding domain (UBZ) of Pol is essential to prevent 8-oxoG-induced mutagenesis but only in conjunction with a functional PCNA-binding domain (PIP). We propose that PCNA is ubiquitylated during the repair synthesis reaction after the MMR-dependent excision of adenine incorporated opposite to 8-oxoG. Monoubiquitylation of PCNA would favor the recruitment of Pol thereby allowing error-free incorporation of dCMP opposite to 8-oxoG. This study suggests that Pol and the post-replication repair (PRR) machinery can also prevent mutagenesis at DNA lesions that do not stall replication forks.
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