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Published online December 31, 2007
doi:10.1083/jcb.200706150
The Journal of Cell Biology, Vol. 179, No. 7, 1337-1345
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Jørgensen et al.
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 The histone methyltransferase SET8 is required for S-phase progression

Stine Jørgensen1, Ingegerd Elvers3, Morten Beck Trelle4, Tobias Menzel1, Morten Eskildsen1, Ole Nørregaard Jensen4, Thomas Helleday3,5, Kristian Helin1,2, and Claus Storgaard Sørensen1

1 Biotech Research and Innovation Centre and 2 Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen N, Denmark
3 Department of Genetics, Microbiology, and Toxicology, Stockholm University, S-10691 Stockholm, Sweden
4 Centre for Epigenetics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark
5 Radiation Oncology and Biology, University of Oxford, Oxford OX3 7LJ, England, UK

Correspondence to Kristian Helin: kristian.helin{at}bric.dk; or Claus Storgaard Sørensen: css{at}bric.dk

Chromatin structure and function is influenced by histone posttranslational modifications. SET8 (also known as PR-Set7 and SETD8) is a histone methyltransferase that monomethylates histonfe H4-K20. However, a function for SET8 in mammalian cell proliferation has not been determined. We show that small interfering RNA inhibition of SET8 expression leads to decreased cell proliferation and accumulation of cells in S phase. This is accompanied by DNA double-strand break (DSB) induction and recruitment of the DNA repair proteins replication protein A, Rad51, and 53BP1 to damaged regions. SET8 depletion causes DNA damage specifically during replication, which induces a Chk1-mediated S-phase checkpoint. Furthermore, we find that SET8 interacts with proliferating cell nuclear antigen through a conserved motif, and SET8 is required for DNA replication fork progression. Finally, codepletion of Rad51, an important homologous recombination repair protein, abrogates the DNA damage after SET8 depletion. Overall, we show that SET8 is essential for genomic stability in mammalian cells and that decreased expression of SET8 results in DNA damage and Chk1-dependent S-phase arrest.

Abbreviations used in this paper: DSB, double-strand break; PCNA, proliferating cell nuclear antigen; PI, propidium iodide; RPA, replication protein A.


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