SIRT1 deacetylates APE1 and regulates cellular base excision repair.
SIRT1 deacetylates APE1 and regulates cellular base excision repair.
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DOI：
10.1093/nar/gkp1039
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发表时间：
2010-01
影响因子：
14.9
通讯作者：
Irani K
中科院分区：
文献类型：
--
作者：
Yamamori T;DeRicco J;Naqvi A;Hoffman TA;Mattagajasingh I;Kasuno K;Jung SB;Kim CS;Irani K
脱嘌呤/脱嘧啶核酸内切酶-1（Apurinic/apyrimidinic endonuclease-1，APE 1）是碱基切除修复（base excision repair，BER）途径中的一种重要酶。在这里，我们表明APE 1是SIRTUIN 1（SIRT 1）蛋白脱乙酰酶的靶点。SIRT 1与APE 1相关，并且这种相关性随着遗传毒性应激而增加。SIRT 1在体外和体内靶向赖氨酸6和7使APE 1脱乙酰基。遗传毒性损伤刺激APE 1的赖氨酸乙酰化，其通过SIRT 1的转录上调来拮抗。SIRT 1的敲除增加了细胞脱碱基DNA含量，使细胞对遗传毒性应激诱导的死亡敏感，而这种脆弱性可通过APE 1的过表达来挽救。白藜芦醇激活SIRT 1可促进APE 1与BER蛋白X射线交叉互补1（XRCC 1）的结合，而烟酰胺（NAM）抑制SIRT 1可降低这种相互作用。遗传毒性损伤还增加APE 1与XRCC 1的结合，并且这种增加被NAM或SIRT 1的敲低抑制。最后，白藜芦醇增加了XRCC 1相关蛋白复合物中的APE活性，而NAM或SIRT 1的敲低抑制了这种DNA修复活性。这些发现将APE 1确定为SIRT 1的新蛋白靶点，并表明SIRT 1通过调节BER途径在维持基因组完整性方面发挥重要作用。
Apurinic/apyrimidinic endonuclease-1 (APE1) is an essential enzyme in the base excision repair (BER) pathway. Here, we show that APE1 is a target of the SIRTUIN1 (SIRT1) protein deacetylase. SIRT1 associates with APE1, and this association is increased with genotoxic stress. SIRT1 deacetylates APE1 in vitro and in vivo targeting lysines 6 and 7. Genotoxic insults stimulate lysine acetylation of APE1 which is antagonized by transcriptional upregulation of SIRT1. Knockdown of SIRT1 increases cellular abasic DNA content, sensitizing cells to death induced by genotoxic stress, and this vulnerability is rescued by overexpression of APE1. Activation of SIRT1 with resveratrol promotes binding of APE1 to the BER protein X-ray cross-complementing-1 (XRCC1), while inhibition of SIRT1 with nicotinamide (NAM) decreases this interaction. Genotoxic insult also increases binding of APE1 to XRCC1, and this increase is suppressed by NAM or knockdown of SIRT1. Finally, resveratrol increases APE activity in XRCC1-associated protein complexes, while NAM or knockdown of SIRT1 suppresses this DNA repair activity. These findings identify APE1 as a novel protein target of SIRT1, and suggest that SIRT1 plays a vital role in maintaining genomic integrity through regulation of the BER pathway.
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影响因子：
64.5
作者：
Oberdoerffer P;Michan S;McVay M;Mostoslavsky R;Vann J;Park SK;Hartlerode A;Stegmuller J;Hafner A;Loerch P;Wright SM;Mills KD;Bonni A;Yankner BA;Scully R;Prolla TA;Alt FW;Sinclair DA
通讯作者：
Sinclair DA
DOI：
10.1165/ajrcmb.25.6.f220
发表时间：
2001-12-01
影响因子：
6.4
作者：
Flaherty, DM;Monick, MM;Hunninghake, GW
通讯作者：
Hunninghake, GW
影响因子：
16
作者：
Cohen, HY;Lavu, S;Sinclair, DA
通讯作者：
Sinclair, DA
影响因子：
64.5
作者：
Murayama, Akiko;Ohmori, Kazuji;Yanagisawa, Junn
通讯作者：
Yanagisawa, Junn
影响因子：
56.9
作者：
Brunet, A;Sweeney, LB;Greenberg, ME
通讯作者：
Greenberg, ME