HDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130.
HDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130.
复制标题
DOI：
10.1038/s41467-018-03096-0
复制
发表时间：
2018-02-22
影响因子：
16.6
通讯作者：
Krämer OH
中科院分区：
文献类型：
--
作者：
Göder A;Emmerich C;Nikolova T;Kiweler N;Schreiber M;Kühl T;Imhof D;Christmann M;Heinzel T;Schneider G;Krämer OH
检查点激酶感知复制应激以防止DNA损伤。在这里，我们表明，组蛋白去乙酰化酶HDAC 1/HDAC 2维持检查点激酶ATM，CHK 1和CHK 2的磷酸化，细胞周期看门人激酶WEE 1和CDK 1的活性，并诱导肿瘤抑制因子p53响应停滞的DNA复制。因此，HDAC抑制复制应激促进有丝分裂灾难。机制上，HDAC 1和HDAC 2抑制PPP 2 R3 A/PR 130的表达，PPP 2 R3 A/PR 130是三聚体丝氨酸/苏氨酸磷酸酶2（PP 2A）的调节亚基。PR 130的遗传消除揭示了PR 130促进ATM通过PP 2A的去磷酸化。此外，PR 130的消融减缓了G1/S相变，并增加了复制应激时磷酸化CHK 1、复制蛋白A焦点和DNA损伤的水平。因此，应激的PR 130无效细胞对HDAC抑制非常敏感，HDAC抑制消除S期检查点，诱导细胞凋亡并减少同源重组蛋白RAD 51。因此，PR 130控制细胞命运的决定后复制应力。检查点激酶通过调节许多关键调节因子来控制细胞周期进程。在这里，作者展示了HDAC 1和HDAC 2如何通过抑制PR 130（三聚体丝氨酸/苏氨酸磷酸酶2的调节亚基）来调节检查点激酶信号传导。
Checkpoint kinases sense replicative stress to prevent DNA damage. Here we show that the histone deacetylases HDAC1/HDAC2 sustain the phosphorylation of the checkpoint kinases ATM, CHK1 and CHK2, activity of the cell cycle gatekeeper kinases WEE1 and CDK1, and induction of the tumour suppressor p53 in response to stalled DNA replication. Consequently, HDAC inhibition upon replicative stress promotes mitotic catastrophe. Mechanistically, HDAC1 and HDAC2 suppress the expression of PPP2R3A/PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2 (PP2A). Genetic elimination of PR130 reveals that PR130 promotes dephosphorylation of ATM by PP2A. Moreover, the ablation of PR130 slows G1/S phase transition and increases the levels of phosphorylated CHK1, replication protein A foci and DNA damage upon replicative stress. Accordingly, stressed PR130 null cells are very susceptible to HDAC inhibition, which abrogates the S phase checkpoint, induces apoptosis and reduces the homologous recombination protein RAD51. Thus, PR130 controls cell fate decisions upon replicative stress. Checkpoint kinases control cell cycle progression via the regulation of many key regulators. Here the authors demonstrate how HDAC1 and HDAC2 modulate checkpoint kinase signalling via the suppression of PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2.
登录
查看更多内容
影响因子：
6.7
作者：
Brestovitsky A;Nebenzahl-Sharon K;Kechker P;Sharf R;Kleinberger T
通讯作者：
Kleinberger T
影响因子：
11.2
作者：
Khanna A;Kauko O;Böckelman C;Laine A;Schreck I;Partanen JI;Szwajda A;Bormann S;Bilgen T;Helenius M;Pokharel YR;Pimanda J;Russel MR;Haglund C;Cole KA;Klefström J;Aittokallio T;Weiss C;Ristimäki A;Visakorpi T;Westermarck J
通讯作者：
Westermarck J
影响因子：
50.3
作者：
Bhaskara S;Knutson SK;Jiang G;Chandrasekharan MB;Wilson AJ;Zheng S;Yenamandra A;Locke K;Yuan JL;Bonine-Summers AR;Wells CE;Kaiser JF;Washington MK;Zhao Z;Wagner FF;Sun ZW;Xia F;Holson EB;Khabele D;Hiebert SW
通讯作者：
Hiebert SW
影响因子：
3.7
作者：
Dunwell, Thomas L.;Hesson, Luke B.;Latif, Farida
通讯作者：
Latif, Farida
影响因子：
8.8
作者：
Groselj B;Sharma NL;Hamdy FC;Kerr M;Kiltie AE
通讯作者：
Kiltie AE