PPM1G在DNA损伤检验点和纺锤体检验点中的功能研究
摘要
细胞周期检验点是真核细胞内调节细胞周期各个时期转换有序进行的重要调控机制,主要包括DNA损伤检验点、DNA复制检验点和纺锤体检验点等细胞周期检验点。检验点缺陷会导致基因组的不稳定性及最终癌变的发生。蛋白质的磷酸化是一种普遍存在的调节机制,它控制着许过细胞的活动。异常的蛋白质磷酸化与许多人类疾病包括痛症的发生相关,它可能是由于蛋白质的磷酸化作用失调引起的。PPM1G属于蛋白磷酸酶PP2C家族,PPM1G在组织中普遍表达,尤其在睾丸、骨骼肌和心脏中的表达量较高,这种普遍性的表达表明PPM1G可能在各种组织和细胞的正常生命活动中发挥着重要的功能。本文探讨蛋白磷酸酶PPM1G在DNA损伤检验点和纺锤体组装检验点中的功能。
我们发现用RNA干扰技术抑制PPM1G的表达导致DNA损伤诱导的G2/M检验点缺陷,DNA损伤标记物γH2AX的水平在DNA损伤后4小时仍保持较高水平。PPM1G在体外对γH2AX去磷酸化。这些结果提示PPM1G参与DNA损伤诱导的G2/M检验点的调控和DNA修复,γH2AX是PPM1G的底物。
我们还发现用RNA干扰技术抑制PPM1G的表达导致纺锤体毒素Nocodazole或Taxol诱导的纺锤体检验点的失活,同时纺锤体检验点关键基因X编码的RNA和蛋白质水平显著下降。PPM1G和DNA依赖的RNA聚合酶PolII相互作用。这些结果提示PPM1G可能通过对纺锤体检验点关键基因X在转录水平的调控而参与纺锤体检验点的激活。
Cell cycle checkpoints ensure the fidelity of cell division in eukaryotic cells.The main checkpoints include:DNA damage checkpoint,DNA replication checkpoint,and spindle assembly checkpoint.Checkpoint defect may result in genome instability and ultimately lead to tumorigenesis.Protein phosphorylation is a common regulatory mechanism that controls many cellular processes.Aberrant protein phosphorylation that most likely results from deregulated dephosphorylation has been associated with many human diseases,including cancer.PPM1G belongs to the PP2C Family.It is ubiquitously expressed in human tissues,especially prostate,muscle,and heart.This implies that PPM1G may play an important role during normal cellular processes.In this thesis we attempted to explore the functions of PPM1G in DNA damage checkpoint and spindle assembly checkpoint.
We demonstrated inhibition of PPM1G expression by RNAi resulted in a defective DNA damage-induced G2/M checkpoint,andγH2AX levels,which are a marker of DNA damage,retained significantly higher 4 hours after DNA damage in comparision to those in mock-depleted cells.PPM1G dephosphorylatedγH2AX in vitro.These results indicate that PPM1G is involved in DNA damage-induced G2/M checkpoint control and DNA repair,andγH2AX is a substrate of PPM1G..
We also demonstrated that inhibition of PPM1G expression led to defects in the spindle poision nocodazole- or taxol-induced spindle checkpoint actyivation,and was associated with a significant decrease of expression(both mRNA and protein levels) of gene X enssential for spindle assembly checkpoint control.Furthermore,PPM1G interacts with the DNA-dependent RNA polymeraseⅡ.Taken together,PPM1G may be involved in the spindle assembly checkpoint control by transcriptional regulation of the spindle checkpoint essential gene X.
我们发现用RNA干扰技术抑制PPM1G的表达导致DNA损伤诱导的G2/M检验点缺陷,DNA损伤标记物γH2AX的水平在DNA损伤后4小时仍保持较高水平。PPM1G在体外对γH2AX去磷酸化。这些结果提示PPM1G参与DNA损伤诱导的G2/M检验点的调控和DNA修复,γH2AX是PPM1G的底物。
我们还发现用RNA干扰技术抑制PPM1G的表达导致纺锤体毒素Nocodazole或Taxol诱导的纺锤体检验点的失活,同时纺锤体检验点关键基因X编码的RNA和蛋白质水平显著下降。PPM1G和DNA依赖的RNA聚合酶PolII相互作用。这些结果提示PPM1G可能通过对纺锤体检验点关键基因X在转录水平的调控而参与纺锤体检验点的激活。
Cell cycle checkpoints ensure the fidelity of cell division in eukaryotic cells.The main checkpoints include:DNA damage checkpoint,DNA replication checkpoint,and spindle assembly checkpoint.Checkpoint defect may result in genome instability and ultimately lead to tumorigenesis.Protein phosphorylation is a common regulatory mechanism that controls many cellular processes.Aberrant protein phosphorylation that most likely results from deregulated dephosphorylation has been associated with many human diseases,including cancer.PPM1G belongs to the PP2C Family.It is ubiquitously expressed in human tissues,especially prostate,muscle,and heart.This implies that PPM1G may play an important role during normal cellular processes.In this thesis we attempted to explore the functions of PPM1G in DNA damage checkpoint and spindle assembly checkpoint.
We demonstrated inhibition of PPM1G expression by RNAi resulted in a defective DNA damage-induced G2/M checkpoint,andγH2AX levels,which are a marker of DNA damage,retained significantly higher 4 hours after DNA damage in comparision to those in mock-depleted cells.PPM1G dephosphorylatedγH2AX in vitro.These results indicate that PPM1G is involved in DNA damage-induced G2/M checkpoint control and DNA repair,andγH2AX is a substrate of PPM1G..
We also demonstrated that inhibition of PPM1G expression led to defects in the spindle poision nocodazole- or taxol-induced spindle checkpoint actyivation,and was associated with a significant decrease of expression(both mRNA and protein levels) of gene X enssential for spindle assembly checkpoint control.Furthermore,PPM1G interacts with the DNA-dependent RNA polymeraseⅡ.Taken together,PPM1G may be involved in the spindle assembly checkpoint control by transcriptional regulation of the spindle checkpoint essential gene X.
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