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Zeng H , Nanayakkara GK , Shao Y , Fu H , Sun Y , Cueto R , Yang WY , Yang Q , Sheng H , Wu N , Wang L , Yang W , Chen H , Shao L , Sun J , Qin X , Park JY , Drosatos K , Choi ET , Zhu Q , Wang H , Yang X
DNA Checkpoint and Repair Factors Are Nuclear Sensors for Intracellular Organelle Stresses-Inflammations and Cancers Can Have High Genomic Risks
Front Physiol. 2018 May;9 :516
PMID: 29867559    PMCID: PMC5958474    URL: https://www.ncbi.nlm.nih.gov/pubmed/29867559
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Under inflammatory conditions, inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS) which cause DNA damage. If not appropriately repaired, DNA damage leads to gene mutations and genomic instability. DNA damage checkpoint factors (DDCF) and DNA damage repair factors (DDRF) play a vital role in maintaining genomic integrity. However, how DDCFs and DDRFs are modulated under physiological and pathological conditions are not fully known. We took an experimental database analysis to determine the expression of 26 DNA DDCFs and 42 DNA DDRFs in 21 human and 20 mouse tissues in physiological/pathological conditions. We made the following significant findings: (1) Few DDCFs and DDRFs are ubiquitously expressed in tissues while many are differentially regulated.; (2) the expression of DDCFs and DDRFs are modulated not only in cancers but also in sterile inflammatory disorders and metabolic diseases; (3) tissue methylation status, pro-inflammatory cytokines, hypoxia regulating factors and tissue angiogenic potential can determine the expression of DDCFs and DDRFs; (4) intracellular organelles can transmit the stress signals to the nucleus, which may modulate the cell death by regulating the DDCF and DDRF expression. Our results shows that sterile inflammatory disorders and cancers increase genomic instability, therefore can be classified as pathologies with a high genomic risk. We also propose a new concept that as parts of cellular sensor cross-talking network, DNA checkpoint and repair factors serve as nuclear sensors for intracellular organelle stresses. Further, this work would lead to identification of novel therapeutic targets and new biomarkers for diagnosis and prognosis of metabolic diseases, inflammation, tissue damage and cancers.
Zeng, Huihong Nanayakkara, Gayani K Shao, Ying Fu, Hangfei Sun, Yu Cueto, Ramon Yang, William Y Yang, Qian Sheng, Haitao Wu, Na Wang, Luqiao Yang, Wuping Chen, Hongping Shao, Lijian Sun, Jianxin Qin, Xuebin Park, Joon Y Drosatos, Konstantinos Choi, Eric T Zhu, Qingxian Wang, Hong Yang, Xiaofeng R01 HL131460/HL/NHLBI NIH HHS/United States Journal Article Switzerland Front Physiol. 2018 May 11;9:516. doi: 10.3389/fphys.2018.00516. eCollection 2018.