histone methyltransferase SET8 is required for S-phase progression

• Published in: The Journal of cell biology Vol. 179; no. 7; pp. 1337 - 1345
• Main Authors: Jørgensen, Stine, Elvers, Ingegerd, Trelle, Morten Beck, Menzel, Tobias, Eskildsen, Morten, Jensen, Ole Nørregaard, Helleday, Thomas, Helin, Kristian, Sørensen, Claus Storgaard
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 31.12.2007; Rockefeller University Press
• Subjects: Amino Acid Motifs - genetics; Antibodies; B lymphocytes; Biochemistry; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell growth; Cell Line, Tumor; Cell Proliferation; Cellular biology; Checkpoint Kinase 1; Chromatin; DNA; DNA damage; DNA Damage - genetics; DNA Repair - genetics; DNA replication; DNA Replication - genetics; Down-Regulation - genetics; Genomic Instability - genetics; HeLa cells; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones; Humans; NATURAL SCIENCES; NATURVETENSKAP; Proliferating Cell Nuclear Antigen - chemistry; Proliferating Cell Nuclear Antigen - metabolism; Protein Kinases - genetics; Protein Kinases - metabolism; Proteins; Rad51 Recombinase - genetics; Rad51 Recombinase - metabolism; Ribonucleic acid; RNA; RNA Interference - physiology; S Phase - genetics; Small interfering RNA
• ISSN: 0021-9525; 1540-8140; 1540-8140
• DOI: 10.1083/jcb.200706150

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.