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Originally published as Genetics Published Articles Ahead of Print on June 18, 2006.

Genetics, Vol. 173, 1951-1968, August 2006, Copyright © 2006
doi:10.1534/genetics.106.057794

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The RAD6/BRE1 Histone Modification Pathway in Saccharomyces Confers Radiation Resistance Through a RAD51-Dependent Process That Is Independent of RAD18

John C. Game*,1, Marsha S. Williamson*, Tatiana Spicakova{dagger} and J. Martin Brown{dagger}

* Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 and {dagger} Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305

1 Corresponding author: Donner Laboratory, Room 326, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., Berkeley, CA 94720.
E-mail: jcgame{at}lbl.gov

We examine ionizing radiation (IR) sensitivity and epistasis relationships of several Saccharomyces mutants affecting post-translational modifications of histones H2B and H3. Mutants bre1{Delta}, lge1{Delta}, and rtf1{Delta}, defective in histone H2B lysine 123 ubiquitination, show IR sensitivity equivalent to that of the dot1{Delta} mutant that we reported on earlier, consistent with published findings that Dot1p requires H2B K123 ubiquitination to fully methylate histone H3 K79. This implicates progressive K79 methylation rather than mono-methylation in IR resistance. The set2{Delta} mutant, defective in H3 K36 methylation, shows mild IR sensitivity whereas mutants that abolish H3 K4 methylation resemble wild type. The dot1{Delta}, bre1{Delta}, and lge1{Delta} mutants show epistasis for IR sensitivity. The paf1{Delta} mutant, also reportedly defective in H2B K123 ubiquitination, confers no sensitivity. The rad6{Delta}, rad51null, rad50{Delta}, and rad9{Delta} mutations are epistatic to bre1{Delta} and dot1{Delta}, but rad18{Delta} and rad5{Delta} show additivity with bre1{Delta}, dot1{Delta}, and each other. The bre1{Delta} rad18{Delta} double mutant resembles rad6{Delta} in sensitivity; thus the role of Rad6p in ubiquitinating H2B accounts for its extra sensitivity compared to rad18{Delta}. We conclude that IR resistance conferred by BRE1 and DOT1 is mediated through homologous recombinational repair, not postreplication repair, and confirm findings of a G1 checkpoint role for the RAD6/BRE1/DOT1 pathway.




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