DNA damage-induced translocation of the Werner helicase is regulated by acetylation.
Werner syndrome is a rare autosomal recessive disorder involving the premature appearance of features reminiscent of human aging. Werner syndrome occurs by mutation of the WRN gene, encoding a DNA helicase. WRN contributes to the induction of the p53 tumor suppressor protein by various DNA damaging agents. Here we show that UV exposure leads to extensive translocation of WRN from the nucleolus to nucleoplasmic foci in a dose-dependent manner. Ionizing radiation also induces WRN translocation, albeit milder, partially through activation of the ATM kinase. The nucleoplasmic foci to which WRN is recruited display partial colocalization with PML nuclear bodies. The translocation of WRN into nucleoplasmic foci is significantly enhanced by the protein deacetylase inhibitor, Trichostatin A. Moreover, Trichostatin A delays the re-entry of WRN into the nucleolus at late times after irradiation. WRN is acetylated in vivo, and this is markedly stimulated by the acetyltransferase p300. Importantly, p300 augments the translocation of WRN into nucleoplasmic foci. These findings support the notion that WRN plays a role in the cellular response to DNA damage and suggest that the activity of WRN is modulated by DNA damage-induced post-translational modifications of WRN and possibly WRN-interacting proteins.
Blander
Gil
G
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Zalle
Noa
N
Daniely
Yaron
Y
Taplick
Jan
J
Gray
Matthew D
MD
Oren
Moshe
M
D000107:Acetylation; D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D005090:Exodeoxyribonucleases; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology / Q000502:physiology; D053484:RecQ Helicases; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014178:Translocation, Genetic; D014898:Werner Syndrome / Q000235:genetics*; D000071657:Werner Syndrome Helicase
D011994:Recombinant Proteins; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase