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首页> 外文期刊>BMC Molecular Biology >SIRT6 protein deacetylase interacts with MYH DNA glycosylase, APE1 endonuclease, and Rad9–Rad1–Hus1 checkpoint clamp
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SIRT6 protein deacetylase interacts with MYH DNA glycosylase, APE1 endonuclease, and Rad9–Rad1–Hus1 checkpoint clamp

机译：SIRT6蛋白脱乙酰基酶与MYH DNA糖基化酶，APE1核酸内切酶和Rad9–Rad1–Hus1检查点钳位相互作用

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摘要

SIRT6, a member of the NAD+-dependent histone/protein deacetylase family, regulates genomic stability, metabolism, and lifespan. MYH glycosylase and APE1 are two base excision repair (BER) enzymes involved in mutation avoidance from oxidative DNA damage. Rad9–Rad1–Hus1 (9–1–1) checkpoint clamp promotes cell cycle checkpoint signaling and DNA repair. BER is coordinated with the checkpoint machinery and requires chromatin remodeling for efficient repair. SIRT6 is involved in DNA double-strand break repair and has been implicated in BER. Here we investigate the direct physical and functional interactions between SIRT6 and BER enzymes. We show that SIRT6 interacts with and stimulates MYH glycosylase and APE1. In addition, SIRT6 interacts with the 9-1-1 checkpoint clamp. These interactions are enhanced following oxidative stress. The interdomain connector of MYH is important for interactions with SIRT6, APE1, and 9–1–1. Mutagenesis studies indicate that SIRT6, APE1, and Hus1 bind overlapping but different sequence motifs on MYH. However, there is no competition of APE1, Hus1, or SIRT6 binding to MYH. Rather, one MYH partner enhances the association of the other two partners to MYH. Moreover, APE1 and Hus1 act together to stabilize the MYH/SIRT6 complex. Within human cells, MYH and SIRT6 are efficiently recruited to confined oxidative DNA damage sites within transcriptionally active chromatin, but not within repressive chromatin. In addition, Myh foci induced by oxidative stress and Sirt6 depletion are frequently localized on mouse telomeres. Although SIRT6, APE1, and 9-1-1 bind to the interdomain connector of MYH, they do not compete for MYH association. Our findings indicate that SIRT6 forms a complex with MYH, APE1, and 9-1-1 to maintain genomic and telomeric integrity in mammalian cells.
机译：SIRT6是NAD +依赖的组蛋白/蛋白质脱乙酰基酶家族的成员，可调节基因组稳定性，代谢和寿命。 MYH糖基化酶和APE1是两种碱基切除修复（BER）酶，参与避免氧化DNA损伤的突变。 Rad9–Rad1–Hus1（9–1–1）检查点钳位可促进细胞周期检查点信号传导和DNA修复。 BER与检查点机器配合使用，并且需要染色质重塑才能有效修复。 SIRT6参与DNA双链断裂修复，并与BER有关。在这里，我们调查SIRT6和BER酶之间的直接物理和功能相互作用。我们显示SIRT6与MYH糖基化酶和APE1相互作用并刺激它。此外，SIRT6与9-1-1检查点夹具相互作用。这些相互作用在氧化应激后得以增强。 MYH的域间连接器对于与SIRT6，APE1和9–1–1的交互非常重要。诱变研究表明，SIRT6，APE1和Hus1结合MYH上重叠但不同的序列基序。但是，不存在与MYH绑定的APE1，Hus1或SIRT6竞争。而是，一个MYH合作伙伴增强了另外两个合作伙伴与MYH的联系。此外，APE1和Hus1共同起作用以稳定MYH / SIRT6复合物。在人类细胞内，MYH和SIRT6被有效地募集到转录活性染色质内的氧化DNA损伤位点，而不是抑制染色质内。此外，由氧化应激和Sirt6耗竭诱导的Myh病灶通常位于小鼠端粒上。尽管SIRT6，APE1和9-1-1绑定到MYH的域间连接器，但它们不竞争MYH关联。我们的发现表明，SIRT6与MYH，APE1和9-1-1形成复合物，以维持哺乳动物细胞中的基因组和端粒完整性。

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