DNA damage triggers tubular endoplasmic reticulum extension to promote apoptosis by facilitating ER-mitochondria signaling  

作　　者：Pengli Zheng Qingzhou Chen Xiaoyu Tian Nannan Qian Peiyuan Chai Bing Liu Junjie Hu Craig Blackstone Desheng Zhu Junlin Teng Jianguo Chen 

机构地区：[1]Key Laboratory. of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China [2]Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National institutes of Health, Bethesda, Maryland 20892, USA [3]College of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China [4]Center for Quantitative Biology, Peking University, Beijing 100871, China [5]National Laboratory of Macromolecules, institute of Biophysics, Chinese Academy of Science, Beijing 100871, China [6]Department of Genetics and Cell Biology, College of Life Sciences, Nankai University and Tianjin Key Laboratory of Protein Sciences, Tianjin 300071, China [7]Laboratory Animal Research Center, Peking University, Beijing 100871, China

出　　处：《Cell Research》2018年第8期833-854,共22页细胞研究（英文版）

基　　金：We thank Dr. Wenling Han at the School of Basic Medical Sciences, Peking University for kindly providing PANC1, AsPC1, BxPc3 and Mia PaCa 2 cells; Dr. Jingwei Xiong at the Institute of Molecular Medicine of Peking University for providing Cas9 and gRNA plasmids; Dr. Yulong Li at the College of Life Sciences of Peking University for providing the mTagBFP2, R-GECO12 and GCaMP6s plasmids; Dr. Qi Ouyang at the Center for Quantitative Biology of Peking University for the p53 plasmid; Dr. Victor W. Hsu at Harvard University for anti-β-COP antibody; Dr. Gyorgy Hajnoczky at the Department of Pathology, Anatomy and Cell Biology of Thomas Jefferson University for the coding sequence of yeast U8C6; Chunyan Shah and Ming Ou at the Core Facilities of Life Sciences of Peking University for confocal microscopy imaging and image processing; and Liying Du and Hongxia Lu at the Core Facilities of Life Sciences of Peking University for flow cytometnj and statistical ana｜ys~s. This work was supported by the Nationa｜ Natural Science Foundation of＇China （NSFC） （31671392 and 31471280）, the National Key Research and Development Program of China, Stem Cell and Translational Research （2016YFA0100501）, and the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, US National institutes of Health.

摘　　要：The endoplasmic reticulum （ER） is composed of the nuclear envelope, perinuclear sheets and a peripheral tubular network. The peripheral ER and mitochondria form tight contacts at specific subdomains, which coordinate the functions of the two organelles and are required for multiple cellular processes such as Ca2＋ transfer and apoptosis. However, it is largely unknown how ER morphology and ER-mitochondria signaling are dynamically regulated under different physiological or pathological conditions such as DNA damage. Here we show that the peripheral, tubular ER undergoes significant extension in response to DNA damage, and that this process is dependent on p53-mediated transcriptional activation of the ER-shaping proteins REEP1, REEP2 and EI24 （alias PIG8）. This promotes the formation of ER-mitochondria contacts through EI24 and the mitochondrial outer membrane protein VDAC2, facilitates Ca2＋ transfer from ER to mitochondria and promotes DNA damage-induced apoptosis. Thus, we identify a unique DNA damage response pathway involving alterations in ER morphology, ER-mitochondria signaling, and apoptosis.

关 键 词：APOPTOSIS Endoplasmic reticulum MITOCHONDRIA 

分 类 号：Q523[生物学—生物化学] X503.2[环境科学与工程—环境工程]