title: DNA damage signaling triggers degradation of histone methyltransferases through APC/C(Cdh1) in senescent cells.
abstract: Both the DNA damage response (DDR) and epigenetic mechanisms play key roles in the implementation of senescent phenotypes, but very little is known about how these two mechanisms are integrated to establish senescence-associated gene expression. Here we show that, in senescent cells, the DDR induces proteasomal degradation of G9a and GLP, major histone H3K9 mono- and dimethyltransferases, through Cdc14B- and p21(Waf1/Cip1)-dependent activation of APC/C(Cdh1) ubiquitin ligase, thereby causing a global decrease in H3K9 dimethylation, an epigenetic mark for euchromatic gene silencing. Interestingly, induction of IL-6 and IL-8, major players of the senescence-associated secretory phenotype (SASP), correlated with a decline of H3K9 dimethylation around the respective gene promoters and knockdown of Cdh1 abolished IL-6/IL-8 expression in senescent cells, suggesting that the APC/C(Cdh1)-G9a/GLP axis plays crucial roles in aspects of senescent phenotype. These findings establish a role for APC/C(Cdh1) and reveal how the DDR integrates with epigenetic processes to induce senescence-associated gene expression.
authors.affiliation: Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Takahashi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Imai
authors.forename: Kimi
authors.initials: K
authors.lastname: Yamakoshi
authors.forename: Shinji
authors.initials: S
authors.lastname: Kuninaka
authors.forename: Naoko
authors.initials: N
authors.lastname: Ohtani
authors.forename: Shin
authors.initials: S
authors.lastname: Yoshimoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hori
authors.forename: Makoto
authors.initials: M
authors.lastname: Tachibana
authors.forename: Emma
authors.initials: E
authors.lastname: Anderton
authors.forename: Takashi
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Shinkai
authors.forename: Gordon
authors.initials: G
authors.lastname: Peters
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Eiji
authors.initials: E
authors.lastname: Hara
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism / Q000502:physiology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D004249:DNA Damage; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006649:Histocompatibility Antigens / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D015398:Signal Transduction; D043743:Ubiquitin-Protein Ligase Complexes / Q000502:physiology*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D006649:Histocompatibility Antigens; D006657:Histones; D000076983:Histone Methyltransferases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; C474200:CDC14B protein, human; D054637:Dual-Specificity Phosphatases