本文關鍵詞： 衰老 Lamin A CK2 HP1 DNA損傷　出處：《深圳大學》2017年碩士論文　論文類型：學位論文

【摘要】：衰老是一種生理功能的漸進性缺失的過程,在細胞水平表現(xiàn)為自我修復能力的減退和不可逆的生長停滯。其主要原因包括DNA損傷的累積、端粒的縮短和INK4a/ARF激活等。HGPS早老癥是研究衰老機制的重要模型,Lamin基因的第11號外顯子1824堿基位點C突變?yōu)門,導致lamin A的加工缺失50個氨基酸序列從而引發(fā)HGPS早老癥。異染色質蛋白HP1(Heterochromatin Protein 1)是維持異染色質形成的重要組成部分,近年來研究發(fā)現(xiàn)HP1可以調控ATM-KAP-1介導的DNA損傷修復通路。CK2作為一種廣泛分布于真核生物的保守絲氨酸/蘇氨酸/酪氨酸蛋白激酶,調控細胞的信號轉導、生存、衰老及凋亡。以往研究發(fā)現(xiàn)Zmpste24-缺陷型細胞在發(fā)生DNA損傷后HP1αT50磷酸化水平比野生型細胞明顯偏低和延遲。并且利用si RNA干擾HP1α降低其表達水平后,Zmpste24-缺陷型細胞對DNA損傷反應的應答有所改善。本文在此基礎上利用Zmpste24-缺陷早老小鼠模型為研究對象,探究在早老模型中蛋白激酶CK2調控HP1α影響DNA損傷修復過程,研究發(fā)現(xiàn):1.HP1αT50位點的突變會影響異染色質對DNA損傷的應答;2.CK2是調控HP1αT50位點磷酸化的關鍵激酶;3.核纖層蛋白Lamin A與CK2存在相互作用,并介導其參與異染色質DNA損傷應答;4.在Zmpste24-缺陷型早老細胞中,CK2酶活性降低,導致DNA損傷堆積;5.小分子藥物TBB抑制早老細胞CK2酶活性,導致細胞DNA損傷應答障礙,會促進早老細胞凋亡。總結以上實驗結果,我們得出結論:1.lamin A-CK2α-HP1α通路參與早老細胞DNA損傷應答過程;2.抑制早老細胞CK2酶活性,早老細胞凋亡水平升高,細胞衰老分子標志物P16表達水平明顯降低。因此,根據(jù)本論文的研究結果提示:抑制早老細胞CK2酶活性,會阻礙早老細胞中l(wèi)amin A-CK2α-HP1α通路參與DNA損傷應答過程,導致細胞DNA損傷堆積,加速早老細胞凋亡,有利于清除衰老的細胞,達到抗衰老目的。
[Abstract]:Aging is a process of progressive loss of physiological function, which is characterized by a decline in self-repair and irreversible growth at the cellular level. The main causes include the accumulation of DNA damage. Telomere shortening and INK4a/ARF activation. HGPS-based early-aging syndrome is an important model for the study of aging mechanism. The 1824 base site C in exon 11 of the Lamin gene mutates to T, resulting in the deletion of 50 amino acid sequences in the processing of lamin A and the initiation of HGPS premature disease. Heterochromatin protein HP1(Heterochromatin Protein 1 is an important component of maintaining heterochromatin formation. In recent years, it has been found that HP1 can regulate DNA damage repair pathway mediated by ATM-KAP-1. CK2 is a conserved serine / threonine / tyrosine protein kinase widely distributed in eukaryotes, regulating cell signal transduction and survival. Senescence and apoptosis. Previous studies have found that the phosphorylation level of HP1 偽 T50 in Zmpste24- deficient cells after DNA damage is significantly lower and delayed than that of wild type cells, and that the expression level of HP1 偽 in Zmpste24- deficient cells is significantly lower than that in wild-type cells after HP1 偽 expression is reduced by si RNA. On the basis of this, the Zmpste24- deficient early aging mice model was used as the research object. To explore the effect of protein kinase CK2 on DNA damage and repair in the early aging model by regulating HP1 偽. It was found that the mutation at 1: 1 HP1 偽 T50 site affected the response of heterochromatin to DNA damage. CK2 was the key kinase to regulate the phosphorylation of HP1 偽 T50 site. The nuclear fiber laminin Lamin A interacted with CK2. In Zmpste24- deficient early aged cells, the activity of CK2 decreased, which led to the accumulation of DNA damage. The small molecular drug TBB inhibited the activity of CK2 enzyme in the early aged cells and led to the impairment of DNA damage in the cells. Conclusion: 1. Lamin A-CK2 偽 -HP1 偽 pathway plays an important role in the process of DNA damage response. 2. Inhibition of CK2 enzyme activity and increase of apoptosis level in early aging cells. The expression of P16, a molecular marker of cell senescence, was significantly decreased. Therefore, according to the results of this study, the inhibition of CK2 enzyme activity in the aged cells may hinder the lamin A-CK2 偽 -HP1 偽 pathway in the early aging cells to participate in the process of DNA damage response. It can cause DNA damage and accelerate the apoptosis of early aging cells, which is helpful to clear the aging cells and achieve the purpose of anti-aging.
【學位授予單位】：深圳大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R339.38

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