DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics.
Chromatin reorganization plays an important role in DNA repair, apoptosis, and cell cycle checkpoints. Among proteins involved in chromatin reorganization, TIP60 histone acetyltransferase has been shown to play a role in DNA repair and apoptosis. However, how TIP60 regulates chromatin reorganization in the response of human cells to DNA damage is largely unknown. Here, we show that ionizing irradiation induces TIP60 acetylation of histone H2AX, a variant form of H2A known to be phosphorylated following DNA damage. Furthermore, TIP60 regulates the ubiquitination of H2AX via the ubiquitin-conjugating enzyme UBC13, which is induced by DNA damage. This ubiquitination of H2AX requires its prior acetylation. We also demonstrate that acetylation-dependent ubiquitination by the TIP60-UBC13 complex leads to the release of H2AX from damaged chromatin. We conclude that the sequential acetylation and ubiquitination of H2AX by TIP60-UBC13 promote enhanced histone dynamics, which in turn stimulate a DNA damage response.
Ikura
Tsuyoshi
T
Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryoumachi 2-1, Aobaku Sendai 980-8575, Japan. ikurat@mail.tains.tohoku.ac.jp
Tashiro
Satoshi
S
Kakino
Akemi
A
Shima
Hiroki
H
Jacob
Naduparambil
N
Amunugama
Ravindra
R
Yoder
Kristine
K
Izumi
Shunsuke
S
Kuraoka
Isao
I
Tanaka
Kiyoji
K
Kimura
Hiroshi
H
Ikura
Masae
M
Nishikubo
Shuichi
S
Ito
Takashi
T
Muto
Akihiko
A
Miyagawa
Kiyoshi
K
Takeda
Shunichi
S
Fishel
Richard
R
Igarashi
Kazuhiko
K
Kamiya
Kenji
K
D000107:Acetylation; D000818:Animals; D002843:Chromatin / Q000378:metabolism*; D004249:DNA Damage; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D010766:Phosphorylation; D011839:Radiation, Ionizing; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
D002843:Chromatin; C468783:H2AX protein, human; D006657:Histones; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes
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