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CELL DEATH AND CELL-CYCLE CHECKPOINT PATHWAYS DURING DNA DAMAGE
JIA Hong-Ti （贾弘禔）
DEPT BIOCHEM MOL BIOL
HSC, Peking Univ
******@
DNA损伤时细胞死亡和细胞周期监控点（调控基本）信号路径
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1. 有哪些原因可引发DNA损伤？DNA损伤结局怎样？
？用什么方法测定？
3. 简述MicroRNA在DDR中作用。（听完本讲座，结合自己研究课题和文件检索）试举一例（可能）与自己工作领域相关MicroRNA功效及其生物学或临床意义。
、G2/M checkpoint 基本信号通路主要分子成份。
5. 程序性细胞死亡（PCD）都有哪些形式？I型（凋亡）、II型（自噬）（自噬定义）PCD主要形态学特征怎样？怎样检测或判定？其基本信号通路所包括主要激活分子是什么？各有何意义？
本讲基本要求——思索题
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诱导DNA损伤与细胞死亡原因*——
各种射线照射/光动力学治疗（光敏反应）
化疗药品/细胞毒、基因毒试剂
缺血/缺氧/氧化应激
血清/营养因子/氨基酸撤出
营养过剩
过分兴奋/刺激
中毒/钙超载
感染/炎症
其它
* 常伴有或直接、间接引发DNA损伤
该讲普遍意义——
各种原因相关DNA损伤引发细胞死亡和细胞周期阻滞
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THE PLETHORA OF DAMAGES IN DNA
(DNA损伤多样性/复杂性）
THE CONSEQUENCES OF DNA INJURY
(DNA损伤结局)
3. CELL-CYCLE CHECKPOINT PATHWAYS
(细胞周期监控点基本信号路径)
4. PROGRAMMED (REGULATED) CELL DEATH (程序性细胞死亡,PCD)
本讲提要
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1. A PLETHORA OF DAMAGES IN DNA
A PERPLEXING DIVERSITY OF DNALESIONS ARISES FROM THREE MAIN CAUSES
Environmental agents (环境原因)
Products of normal cellular metabolism in mitochondrion（线粒体代谢产物
——ROS）
Some chemical bonds in DNA spontaneously disintegrate under physiological conditions （DNA自发裂解）
(A) Environmental Agents: ultraviolet (UV) , ionizing radiation …
(环境原因) genotoxic chemicals
virus infection
Alterations in DNA structure: Adjacent thymine dimer
DNA single stranded breaks (DNA SSBs)
DNA double stranded breaks (DNA DSBs)
Cross-linking (intra- and inter-cross-linking)
…
DNA损伤多样性及主要诱因
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(B) Products of Normal Cellular Metabolism in Mitochondrion:
(线粒体代谢产物——ROS）
Reactive oxygen species (ROS) derived from oxidative respiration and products of lipid peroxidation.
Oxidative modifications in DNA. ., 8-OxoG
Antioxidant defence system composed of enzymatic (superoxide dismutase/SOD, catalase, glutathione peroxidase/GPx and peroxyredoxins/GR) and low molecular-mass scavengers (such as glutathione/GSH).
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Fig- Production of ROS and antioxidant defence systems in hippocampal neurons under kainate-induced oxidative stress. (Li SY et al. Free Rad Biol Med, 48:597-608, )
ROS产生——海人酸引发神经元过分兴奋(举例)
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Fig- Genotoxic chemical exposure induces DNA DSBs. (A) Identification of DNA DSBs by PFGE. (B) Immunocytochemical staining gamma-H2AX foci. (C) Testing gamma-H2AX (H2AX-Ser139) by Western blotting. (Yang SY, et al. Biochem Pharmacol, 77: 433-443, )
DNA损伤——双链断裂(3种)判定（举例）
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Fig- The effects of kanic acid-induced ROS production on the integrity of the genome in cultured neurons. The genomic DNA damage was tested using fluorescein isothiocyanate (FITC)-conjugated avidin, which binds to 8-oxodeoxyguanosine (8-oxodG) with a structural similarity to biotin (Radisky DC et al. Nature, . 436: 123-127)
抗生物素蛋白检测DNA氧化损伤（8-O-鸟苷）判定（举例）
彗星试验检测DSBs （举例）
Fig- Comet assay. To score the percentage of DNA in the tail, the image analysis system was used . The percentage of comet tail area (DNA tail area/total DNA area) and the comet tail length (from the center of the DNA head to the end of the DNA tail) were analyzed in 50 cells for one slide. (Anderson D et al. Mutat Res1994; 307:261-271)
Con
μM
2 μM
10 μM
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