Stwl modifies chromatin compaction and is required to maintain DNA integrity in the presence of perturbed DNA replication.
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.
Yi
Xia
X
Department of Radiation and Stress Cell Biology, Division of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands.
de Vries
Hilda I
HI
Siudeja
Katarzyna
K
Rana
Anil
A
Lemstra
Willy
W
Brunsting
Jeanette F
JF
Kok
Rob M
RM
Smulders
Yvo M
YM
Schaefer
Matthias
M
Dijk
Freark
F
Shang
Yongfeng
Y
Eggen
Bart J L
BJ
Kampinga
Harm H
HH
Sibon
Ody C M
OC
D000818:Animals; D000071877:Checkpoint Kinase 1; D002843:Chromatin / Q000378:metabolism* / Q000648:ultrastructure; D055012:Chromosomal Position Effects / Q000187:drug effects; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D016153:Genes, Suppressor; D006570:Heterochromatin / Q000378:metabolism / Q000648:ultrastructure; D006657:Histones / Q000378:metabolism; D006918:Hydroxyurea / Q000494:pharmacology; D007814:Larva / Q000187:drug effects / Q000254:growth & development; D008239:Lysine / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014921:Wings, Animal / Q000033:anatomy & histology / Q000187:drug effects / Q000648:ultrastructure
D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D006570:Heterochromatin; D006657:Histones; D014157:Transcription Factors; C452193:heterochromatin protein 1, Drosophila; C098675:stwl protein, Drosophila; D004247:DNA; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D008239:Lysine; D006918:Hydroxyurea