ヒストン脱アセチル化酵素SIRT1は心筋細胞においてヒストンH2AXを脱アセチル化を介して適切なDNA損傷反応をもたらす

DOI Web Site

書誌事項

タイトル別名
  • SIRT1, a histone deacetylase, mediates the proper DNA damage response via histone H2AX deacetylation in the cardiomyocyte.

抄録

<p>Background and hypothesis: We recently found that knockout of SIRT1, a histone deacetylase, aggravates doxorubicin (DOX)-induced cardiotoxicity. We hypothesized that SIRT1 regulates DNA damage response (DDR) to attenuate cardiotoxicity.</p><p>Methods and Results: Wild type (WT) and SIRT1 knockout in the cardiomyocyte (SIRT1-cKO) mice were treated with vehicle or DOX (4 IP injections of 5 mg/kg/week) starting at 3-month-old.  Immunoblotting showed that DOX increased myocardial levels of phospho-Ser139-histone H2AX (pS139-H2AX), a critical mediator of DDR, in WT. However, the increase in pS139-H2AX by DOX was attenuated in SIRT1-cKO. The nucleus with DNA fragmentation evaluated by TUNEL staining was more increased by DOX in SIRT1-cKO than WT (0.384 vs 0.194%).  In H9c2 cardiomyocytes, cell death after DOX was enhanced by knockdown (KD) of SIRT1. DOX increased pS139H2AX levels, which was attenuated by SIRT1-KD. Pharmacological inhibition or KD of SIRT1 increased acetyl-Lys5 (K5) H2AX level. Furthermore, S139-H2AX phosphorylation by DOX was attenuated in a mutant H2AX with acetylation mimic of K5 (K5Q-H2AX) compared with that in WT-H2AX.</p><p>Conclusion: These suggest that deacetylation of H2AX at K5 by SIRT1 plays a critical role in Ser139-H2AX phosphorylation to promotes proper DDR and therefore to attenuate cardiotoxicity.</p>

収録刊行物

キーワード

詳細情報 詳細情報について

問題の指摘

ページトップへ