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Nucleic Acids Research, 2003, Vol. 31, No. 21 6085-6095
© 2003 Oxford University Press

Article

8-Hydroxyguanine in a mutational hotspot of the c-Ha-ras gene causes misreplication, ‘action-at-a-distance’ mutagenesis and inhibition of replication

Pawel Jaloszynski, Chikahide Masutani1, Fumio Hanaoka1,2, Ana Blanco Perez and Susumu Nishimura*

Banyu Tsukuba Research Institute in Collaboration with Merck Research Laboratories, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan, 1 Graduate School of Frontier Biosciences, Osaka University and CREST, Japan Science and Technology Corporation, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan and 2 Cellular Physiology Laboratory, Discovery Research Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

*To whom correspondence should be addressed. Tel: +81 29 877 2003; Fax: +81 29 877 2034; Email: nismrasm{at}banyu.co.jp

Mutations in particular codons of c-Ha-ras have a strong activating potential, and an activated ras oncogene has been found in a number of human cancers. Using fragments of the human c-Ha-ras gene containing 8-hydroxyguanine (8-OH-G) in codon 12, we provide evidence for highly complex biochemical events leading to activation of the oncogene. Replication with DNA polymerases {alpha} (Pol{alpha}) and ß (Polß) led to misincorporation of dAMP, while DNA polymerase {eta} (Pol{eta}) caused additional insertion of dGMP. For the first time we report an ‘action-at-a-distance’ mutagenic effect for Pol{eta}. Replication catalyzed by this enzyme resulted in misincorporating dAMP, dTMP and dGMP opposite non-oxidized guanine 3'-flanked by 8-OH-G. Interestingly, two adjacent 8-OH-G residues greatly relaxed the specificity of Pol{eta}, which in this system was able to incorporate all four nucleotides. Moreover, two adjacent 8-OH-G residues completely blocked Pol{alpha} and strongly inhibited Polß, whereas Pol{eta} was entirely resistant to this inhibition. These results suggest an important role for Pol{eta} in inducing hypermutability in codon 12. Our observations are important for understanding the consequences of 8-OH-G being positioned within the mutational hot spots of oncogenes, the outcome of which appears to be relatively complex even in minimal in vitro systems.


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