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Vol. 20, Issue 3, 983-994, February 1, 2009

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Stwl Modifies Chromatin Compaction and Is Required to Maintain DNA Integrity in the Presence of Perturbed DNA Replication

Xia Yi^*,,, Hilda I. de Vries^*,,, Katarzyna Siudeja^*, Anil Rana^*, Willy Lemstra^*, Jeanette F. Brunsting^*, Rob M. Kok^||, Yvo M. Smulders^¶, Matthias Schaefer^#, Freark Dijk^@, Yongfeng Shang, Bart J.L. Eggen^**, Harm H. Kampinga^*, and Ody C.M. Sibon^*

*Department of Radiation and Stress Cell Biology, Division of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100083, China; ^||Department of Clinical Chemistry, Free University Medical Center, 1081 HV Amsterdam, The Netherlands; ^¶Department of Internal Medicine and Institute for Cardiovascular Research (ICaR-VU), Free University Medical Center, 1081 HV Amsterdam, The Netherlands; ^#German Cancer Research Center Epigenetics, INF 580, D-69120 Heidelberg, Germany; ^@Department of Cell Biology and Electron Microscopy, Division of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; and **Department of Developmental Genetics, University of Groningen, 9751 NN Groningen, The Netherlands

Submitted June 23, 2008; Revised October 29, 2008; Accepted November 20, 2008
Monitoring Editor: Wendy Bickmore

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.

These authors contributed equally to this work.

Present address: Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Address correspondence to: Ody Sibon (o.c.m.sibon{at}med.umcg.nl)