1. Stwl Modifies Chromatin Compaction and Is Required to Maintain DNA Integrity in the Presence of Perturbed DNA Replication
- Author
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Hilda I. de Vries, Yvo M. Smulders, Harm H. Kampinga, Ody C. M. Sibon, Xia Yi, Willy Lemstra, Freark Dijk, R. M. Kok, Yongfeng Shang, Matthias Schaefer, Anil Rana, Katarzyna Siudeja, Bart J. L. Eggen, Jeanette F. Brunsting, Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Internal medicine, EMGO - Lifestyle, overweight and diabetes, and ICaR - Ischemia and repair
- Subjects
Transcription, Genetic ,Chromosomal Proteins, Non-Histone ,Eukaryotic DNA replication ,Histones ,SACCHAROMYCES-CEREVISIAE ,MAMMALIAN-CELLS ,Heterochromatin ,MIDBLASTULA TRANSITION ,Drosophila Proteins ,Hydroxyurea ,Wings, Animal ,Genes, Suppressor ,Articles ,Chromatin ,DNA-Binding Proteins ,Protein Transport ,Drosophila melanogaster ,STRAND BREAK REPAIR ,Larva ,Female ,Protein Binding ,DNA Replication ,DNA re-replication ,DNA repair ,DNA damage ,Mitosis ,Biology ,Chromosomal Position Effects ,Control of chromosome duplication ,DAMAGE CHECKPOINT ,Animals ,Molecular Biology ,Replication protein A ,Lysine ,DNA replication ,DNA ,Cell Biology ,DNA Methylation ,G2-M DNA damage checkpoint ,Survival Analysis ,GENE ,Molecular biology ,CELL-CYCLE CHECKPOINTS ,DROSOPHILA-MELANOGASTER ,SENSITIVE MUTATIONS ,Checkpoint Kinase 1 ,Mutation ,HISTONE H2AX PHOSPHORYLATION ,Protein Kinases ,Transcription Factors - Abstract
Hydroxyurea, a well-known DNA replication inhibitor, induces cell cycle arrest and intact checkpoint functions are required to survive DNA replication stress induced by this genotoxic agent. Perturbed DNA synthesis also results in elevated levels of DNA damage. It is unclear how organisms prevent accumulation of this type of DNA damage that coincides with hampered DNA synthesis. Here, we report the identification of stonewall (stwl) as a novel hydroxyurea-hypersensitive mutant. We demonstrate that Stwl is required to prevent accumulation of DNA damage induced by hydroxyurea; yet, Stwl is not involved in S/M checkpoint regulation. We show that Stwl is a heterochromatin-associated protein with transcription-repressing capacities. In stwl mutants, levels of trimethylated H3K27 and H3K9 (two hallmarks of silent chromatin) are decreased. Our data provide evidence for a Stwl-dependent epigenetic mechanism that is involved in the maintenance of the normal balance between euchromatin and heterochromatin and that is required to prevent accumulation of DNA damage in the presence of DNA replication stress.
- Published
- 2009
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