The deacetylation-phosphorylation regulation of SIRT2-SMC1A axis as a mechanism of antimitotic catastrophe in early tumorigenesis.
The deacetylation-phosphorylation regulation of SIRT2-SMC1A axis as a mechanism of antimitotic catastrophe in early tumorigenesis.
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SIRT2-SMC1A轴的脱乙酰化-磷酸化调节作为早期肿瘤发生中抗有丝分裂灾难的机制
DOI：
10.1126/sciadv.abe5518
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发表时间：
2021-03
期刊：
影响因子：
13.6
通讯作者：
Cao L
中科院分区：
文献类型：
--
作者：
Yi F;Zhang Y;Wang Z;Wang Z;Li Z;Zhou T;Xu H;Liu J;Jiang B;Li X;Wang L;Bai N;Guo Q;Guan Y;Feng Y;Mao Z;Fan G;Zhang S;Wang C;Cao L;O'Rourke BP;Wang Y;Wu Y;Wu B;You S;Zhang N;Guan J;Song X;Sun Y;Wei S;Cao L
SIRT 2介导的SMC 1A的去乙酰化促进其磷酸化并克服肿瘤细胞存活的致癌应激。在有丝分裂过程中染色体的不适当分布会导致恶性转化。高等真核生物已经进化出一种有丝分裂灾难机制，用于消除有丝分裂无能的细胞;然而，信号级联及其表观遗传调控知之甚少。我们对人类癌组织的分析表明，NAD依赖性脱乙酰酶SIRT 2在各种器官的早期癌中上调。质谱分析显示，SIRT 2与染色体结构维持蛋白1（SMC 1A）相互作用并使其脱乙酰化，然后促进SMC 1A磷酸化以正确驱动有丝分裂。我们进一步证明，SIRT 2活性的抑制或SMC 1A-K579乙酰化的持续增加会导致染色体异常分离，从而诱导癌细胞的有丝分裂灾难并增强其对化疗药物的脆弱性。这些发现表明，SIRT 2-SMC 1A轴通过去乙酰化-磷酸化的调节允许从有丝分裂灾难中逃脱，从而允许早期前体病变克服致癌应激。
SIRT2-mediated deacetylation of SMC1A promotes its phosphorylation and overcomes the oncogenic stress for tumor cell survival. Improper distribution of chromosomes during mitosis can contribute to malignant transformation. Higher eukaryotes have evolved a mitotic catastrophe mechanism for eliminating mitosis-incompetent cells; however, the signaling cascade and its epigenetic regulation are poorly understood. Our analyses of human cancerous tissue revealed that the NAD-dependent deacetylase SIRT2 is up-regulated in early-stage carcinomas of various organs. Mass spectrometry analysis revealed that SIRT2 interacts with and deacetylates the structural maintenance of chromosomes protein 1 (SMC1A), which then promotes SMC1A phosphorylation to properly drive mitosis. We have further demonstrated that inhibition of SIRT2 activity or continuously increasing SMC1A-K579 acetylation causes abnormal chromosome segregation, which, in turn, induces mitotic catastrophe in cancer cells and enhances their vulnerability to chemotherapeutic agents. These findings suggest that regulation of the SIRT2-SMC1A axis through deacetylation-phosphorylation permits escape from mitotic catastrophe, thus allowing early precursor lesions to overcome oncogenic stress.
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影响因子：
4.8
作者：
Hoffmann, Gesine;Breitenbuecher, Frank;Ehrenhofer-Murray, Ann E.
通讯作者：
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