DNA损伤试剂对HeLa细胞的细胞周期检查点的影响
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摘要
p53蛋白参与了细胞周期检查点和DNA修复等多种生命活动中,在维护基因组完整性中发挥重要的作用。多种类型的肿瘤中均发现p53的突变,提示肿瘤细胞体系中DNA损伤检查点的机制可能不同于正常的组织细胞。
为探讨在p53失活的肿瘤细胞中DNA甲基化试剂引发的DNA损伤对于细胞周期的影响,我们将同步化在G1期、S期和G2/M期的HeLa细胞分别进行甲磺酸甲酯(MMS)处理。MMS的处理结果表明,各个时相的细胞周期进程均发生延迟或阻滞,其中S期细胞对药物最为敏感。进一步分子机理研究表明,三个时相中ATM-Chk2和p38 MAPK通路均被激活,但是检查点激酶1(Chk1)仅在S期中被活化,提示Chk1特异地参与了S期的DNA损伤检查点(DNA damage checkpoint)或者DNA复制检查点(DNA replication checkpoint)的作用。为了进一步确定Chk1在S期的检查点功能,我们用专一的小分子抑制剂抑制Chk1的磷酸化,发现被MMS处理的S期细胞能在未完成复制的情况下进行异常的有丝分裂;提示Chk1主要是在HeLa细胞S期的DNA损伤检查点而不是DNA复制检查点发挥其作用。我们还检查了参与G2/M期进程的cyclin B1的表达变化情况,在MMS处理的S期细胞中cyclin B1表达量不能上调,而在加入Chk1抑制剂处理后,cyclin B1则有所增加。这一结果进一步支持DNA损伤S期细胞在Chk1失活时进入异常有丝分裂的推论。我们的研究结果表明,Chk1是MMS诱发的HeLa细胞S期DNA损伤检查点的专一性的重要蛋白激酶;当MMS引发DNA损伤后,上游蛋白激酶对Chk1进行磷酸化,从而激活了S期的DNA损伤检查点,阻止细胞进入G2/M期。由于这一过程不依赖于p53的活性,因此Chk1有可能作为p53失活的肿瘤细胞的药物靶标。
Tumor suppressor protein p53 plays a critical role in the maintenance of genomic stability, participating in many cellular processes such as cell cycle checkpoints and DNA repair. However, half types of human tumor display p53 mutation or function deficience due to virus infection, suggesting that the DNA damage checkpoints in tumor cells may differ from those of normal tissues.
To explore the effect of DNA damage induced by DNA methylating agents on cell cycle progression in p53-deficient tumor cells, synchronized HeLa cells at G1, S or G2/M phases are treated with methyl methanesulfnate (MMS). It is shown that MMS treatment leads to cell cycle arrest or delay in all 3 phases, and S phase cells are the most sensitive. Further study demonstrates that ATM-Chk2 and p38 MAPK signaling pathways are activated in all 3 phases when treated with MMS; interestingly, checkpoint kinase 1 (Chk1) is phosphorylated and activated only in S phase after drug treatment, indicating that Chk1 specifically participates S phase DNA damage chekpoint or DNA replication checkpoint. To identify the role of Chk1 in S phase checkpoints, a small-molecule inhibitor specifically targeting Chk1 is used to inhibit phosphorylation of Chk1. We find that S-phase cells enter into aberrant mitosis without finishing DNA replication, indicating that Chk1 mainly functions in S phase DNA damage checkpoint. Besides, the protein level of cyclin B1, a key component of M phase CDK-cyclin complex, is also examined. MMS treatment inhibits accumulation of cyclin B1 during S phase, and when Chk1 is inhibited, cyclin B1 begins to accumulate again. This further supports the view that DNA-damaged S phase cells enter into premature mitosis when Chk1 is inhibited. Our results demonstrate that Chk1 is a specific kinase which plays an important role in MMS-induced S phase DNA damage checkpoint; MMS induces DNA damage, upstream kinase phosphorylates and activates Chk1, so S phase DNA damage checkpoint is activated to prevent cells entering into G2/M phase. p53 doesn’t participate in this process, and thus Chk1 could be a potential target for p53-deficient tumor therapy.
为探讨在p53失活的肿瘤细胞中DNA甲基化试剂引发的DNA损伤对于细胞周期的影响,我们将同步化在G1期、S期和G2/M期的HeLa细胞分别进行甲磺酸甲酯(MMS)处理。MMS的处理结果表明,各个时相的细胞周期进程均发生延迟或阻滞,其中S期细胞对药物最为敏感。进一步分子机理研究表明,三个时相中ATM-Chk2和p38 MAPK通路均被激活,但是检查点激酶1(Chk1)仅在S期中被活化,提示Chk1特异地参与了S期的DNA损伤检查点(DNA damage checkpoint)或者DNA复制检查点(DNA replication checkpoint)的作用。为了进一步确定Chk1在S期的检查点功能,我们用专一的小分子抑制剂抑制Chk1的磷酸化,发现被MMS处理的S期细胞能在未完成复制的情况下进行异常的有丝分裂;提示Chk1主要是在HeLa细胞S期的DNA损伤检查点而不是DNA复制检查点发挥其作用。我们还检查了参与G2/M期进程的cyclin B1的表达变化情况,在MMS处理的S期细胞中cyclin B1表达量不能上调,而在加入Chk1抑制剂处理后,cyclin B1则有所增加。这一结果进一步支持DNA损伤S期细胞在Chk1失活时进入异常有丝分裂的推论。我们的研究结果表明,Chk1是MMS诱发的HeLa细胞S期DNA损伤检查点的专一性的重要蛋白激酶;当MMS引发DNA损伤后,上游蛋白激酶对Chk1进行磷酸化,从而激活了S期的DNA损伤检查点,阻止细胞进入G2/M期。由于这一过程不依赖于p53的活性,因此Chk1有可能作为p53失活的肿瘤细胞的药物靶标。
Tumor suppressor protein p53 plays a critical role in the maintenance of genomic stability, participating in many cellular processes such as cell cycle checkpoints and DNA repair. However, half types of human tumor display p53 mutation or function deficience due to virus infection, suggesting that the DNA damage checkpoints in tumor cells may differ from those of normal tissues.
To explore the effect of DNA damage induced by DNA methylating agents on cell cycle progression in p53-deficient tumor cells, synchronized HeLa cells at G1, S or G2/M phases are treated with methyl methanesulfnate (MMS). It is shown that MMS treatment leads to cell cycle arrest or delay in all 3 phases, and S phase cells are the most sensitive. Further study demonstrates that ATM-Chk2 and p38 MAPK signaling pathways are activated in all 3 phases when treated with MMS; interestingly, checkpoint kinase 1 (Chk1) is phosphorylated and activated only in S phase after drug treatment, indicating that Chk1 specifically participates S phase DNA damage chekpoint or DNA replication checkpoint. To identify the role of Chk1 in S phase checkpoints, a small-molecule inhibitor specifically targeting Chk1 is used to inhibit phosphorylation of Chk1. We find that S-phase cells enter into aberrant mitosis without finishing DNA replication, indicating that Chk1 mainly functions in S phase DNA damage checkpoint. Besides, the protein level of cyclin B1, a key component of M phase CDK-cyclin complex, is also examined. MMS treatment inhibits accumulation of cyclin B1 during S phase, and when Chk1 is inhibited, cyclin B1 begins to accumulate again. This further supports the view that DNA-damaged S phase cells enter into premature mitosis when Chk1 is inhibited. Our results demonstrate that Chk1 is a specific kinase which plays an important role in MMS-induced S phase DNA damage checkpoint; MMS induces DNA damage, upstream kinase phosphorylates and activates Chk1, so S phase DNA damage checkpoint is activated to prevent cells entering into G2/M phase. p53 doesn’t participate in this process, and thus Chk1 could be a potential target for p53-deficient tumor therapy.
引文
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