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ATR Isomerization in Cellular Responses to UV Damage of DNA

细胞对 DNA 紫外线损伤反应中的 ATR 异构化

基本信息

批准号：
10459421
负责人：
Yue Zou
金额：
$ 39.27万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459421
关键词：
ATR gene Address Adopted Aging Amino Acids Apoptosis Apoptotic BCL2 gene Cancer Biology Cardiovascular Diseases Cell Cycle Progression Cell Death Cell Nucleus Cell Survival Cells Clinic Clinical Trials Complex Cytoplasm DNA DNA Damage DNA Repair DNA damage checkpoint Embryo Exhibits Family Family member Human Isomerism KRP protein Knock-out Laboratories Malignant Neoplasms Malignant neoplasm of ovary Maps Mass Spectrum Analysis Mediating Mitochondria Molecular Conformation Mutant Strains Mice Mutate NIMA Neurodegenerative Disorders Nuclear Organelles Pathway interactions Phosphatidylinositols Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Protein Dephosphorylation Protein Family Protein Footprinting Protein Kinase Proteins Role Signal Transduction Structure Structure-Activity Relationship Study models TREX1 gene Telangiectasis Testing UV carcinogenesis UV induced UV induced DNA damage ataxia telangiectasia mutated protein base cancer prevention cancer therapy carcinogenesis cis trans isomerization cis-trans-Isomerases cytochrome c epidemiology study genome integrity human disease in vivo innovation member mouse model novel novel strategies protein function response therapeutic target tumorigenesis ultraviolet damage

项目摘要

Summary DNA damage is a major cause of human cancers and many other human diseases. In response to DNA damage, cells activate DNA damage response (DDR) pathways such as DNA damage checkpoints, DNA repair, and apoptosis. ATR (ataxia telangiectasia and Rad3-related), a member of the phosphoinositide 3-kinase-related protein kinases (PIKK) family, is a major DNA damage checkpoint protein kinase which plays a critical role in DDR by signaling DNA damage, activating checkpoints, arresting cell cycle progression and facilitating DNA repair to restore DNA integrity. Interestingly, a body of evidence from mouse model and human epidemiologic studies shows that unlike ATM, a closely related ATR-like PIKK family member whose deficiency promotes carcinogenesis, ATR inhibition suppresses carcinogenesis. Moreover, ATR knockout is embryonically lethal. These suggest an involvement of ATR in regulating cell death. Although ATR has been extensively studied as a checkpoint kinase in DDR in the nucleus, little is known about its functions in the cytoplasm or mitochondria, the cellular organelle for activating DNA damage-induced apoptosis. A recent finding from the P.I.’s lab reveals that (a) besides its hallmark nuclear checkpoint functions, ATR is a pro-survival protein functioning directly at mitochondria against UV damage; (b) ATR contains a BH3-like domain that allows ATR to act like a Bcl-2 family protein; (c) importantly, mitochondrial ATR is a prolyl cis-isomeric form of ATR regulated by Pin1 while in contrast, nuclear ATR is a trans-isomeric form of ATR; and finally (d) mitochondria activity of ATR is independent of its checkpoint kinase activity and ATRIP. In this project, we will test the hypotheses that (1) Prolyl isomerization alters the structure of ATR, transforming ATR functions for mitochondria-specific activities to promote cell survival or nuclear functions as a DNA damage checkpoint regulator; (2) Antiapoptotic activity of ATR at mitochondria plays an important role in mediating carcinogenesis in vivo, and thus, suppressing such activity may reduce carcinogenesis/tumorigenesis and provide a strategy for cancer prevention and treatment; and (3) ATR’s trans-isomeric form is required for its DNA damage checkpoint activity, and post- translational modifications of ATR and/or ATR-ATRIP complex formation may play a role in stabilizing ATR in the trans-isomeric form in the nucleus. These hypotheses will be tested in the following specific aims. Aim 1: To define the structure-function relationships of ATR prolyl isomers, and of ATRH-tBid and ATRH- Pin1 interactions; Aim 2: To determine the role of prolyl isomerization in the nuclear functions of ATR; and Aim 3: To determine the in vivo effects of ATR isomers on carcinogenesis and tumorigenesis. The proposed studies represent an innovative effort highly relevant to cancer biology and also having implications in other human diseases such as neurodegenerative and cardiovascular diseases.

总结