p300-mediated acetylation of the Rothmund-Thomson-syndrome gene product RECQL4 regulates its subcellular localization.
RECQL4 belongs to the conserved RecQ family of DNA helicases, members of which play important roles in the maintenance of genome stability in all organisms that have been examined. Although genetic alterations in the RECQL4 gene are reported to be associated with three autosomal recessive disorders (Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes), the molecular role of RECQL4 still remains poorly understood. Here, we show that RECQL4 specifically interacts with the histone acetyltransferase p300 (also known as p300 HAT), both in vivo and in vitro, and that p300 acetylates one or more of the lysine residues at positions 376, 380, 382, 385 and 386 of RECQL4. Furthermore, we report that these five lysine residues lie within a short motif of 30 amino acids that is essential for the nuclear localization of RECQL4. Remarkably, the acetylation of RECQL4 by p300 in vivo leads to a significant shift of a proportion of RECQL4 protein from the nucleus to the cytoplasm. This accumulation of the acetylated RECQL4 is a result of its inability to be imported into the nucleus. Our results provide the first evidence of a post-translational modification of the RECQL4 protein, and suggest that acetylation of RECQL4 by p300 regulates the trafficking of RECQL4 between the nucleus and the cytoplasm.
Dietschy
Tobias
T
Department of Biochemistry, Faculty of Medicine, Terrence Donnelly Centre for Cellular and Biomolecular Research (dCCBR), University of Toronto, Toronto ON, Canada M5S 3E1.
Shevelev
Igor
I
Pena-Diaz
Javier
J
Hühn
Daniela
D
Kuenzle
Sandra
S
Mak
Raymond
R
Miah
Mohammad Fahad
MF
Hess
Daniel
D
Fey
Monika
M
Hottiger
Michael O
MO
Janscak
Pavel
P
Stagljar
Igor
I
D000107:Acetylation; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008239:Lysine; D008969:Molecular Sequence Data; D009154:Mutation; D019913:Nuclear Localization Signals / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D053484:RecQ Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
D019913:Nuclear Localization Signals; D011993:Recombinant Fusion Proteins; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C506731:RECQL4 protein, human; D053484:RecQ Helicases; D008239:Lysine