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Molecular and Cellular Biology, October 2005, p. 8430-8443, Vol. 25, No. 19
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.19.8430-8443.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Role of Dot1-Dependent Histone H3 Methylation in G1 and S Phase DNA Damage Checkpoint Functions of Rad9

Robert Wysocki,1 Ali Javaheri,1 Stéphane Allard,2 Fei Sha,1 Jacques Côté,2 and Stephen J. Kron1*

Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois 60637,1 Laval University Cancer Research Center, Hôtel-Dieu de Québec, Quebec City, Quebec G1R 2J6, Canada2

Received 27 April 2005/ Returned for modification 23 May 2005/ Accepted 6 July 2005

We screened radiation-sensitive yeast mutants for DNA damage checkpoint defects and identified Dot1, the conserved histone H3 Lys 79 methyltransferase. DOT1 deletion mutants (dot1{Delta}) are G1 and intra-S phase checkpoint defective after ionizing radiation but remain competent for G2/M arrest. Mutations that affect Dot1 function such as Rad6-Bre1/Paf1 pathway gene deletions or mutation of H2B Lys 123 or H3 Lys 79 share dot1{Delta} checkpoint defects. Whereas dot1{Delta} alone confers minimal DNA damage sensitivity, combining dot1{Delta} with histone methyltransferase mutations set1{Delta} and set2{Delta} markedly enhances lethality. Interestingly, set1{Delta} and set2{Delta} mutants remain G1 checkpoint competent, but set1{Delta} displays a mild S phase checkpoint defect. In human cells, H3 Lys 79 methylation by hDOT1L likely mediates recruitment of the signaling protein 53BP1 via its paired tudor domains to double-strand breaks (DSBs). Consistent with this paradigm, loss of Dot1 prevents activation of the yeast 53BP1 ortholog Rad9 or Chk2 homolog Rad53 and decreases binding of Rad9 to DSBs after DNA damage. Mutation of Rad9 to alter tudor domain binding to methylated Lys 79 phenocopies the dot1{Delta} checkpoint defect and blocks Rad53 phosphorylation. These results indicate a key role for chromatin and methylation of histone H3 Lys 79 in yeast DNA damage signaling.

* Corresponding author. Mailing address: Center for Molecular Oncology, The University of Chicago, 924 East 57th St., Rm. R320, Chicago, IL 60637. Phone: (773) 834-0250. Fax: (773) 702-4394. E-mail: skron{at}uchicago.edu.

Molecular and Cellular Biology, October 2005, p. 8430-8443, Vol. 25, No. 19
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.19.8430-8443.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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