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
Department of Histology and Embryology, Basic Medical School, Nanchang University, Nanchang, China.
Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.
Front Physiol. 2018 May 11;9:516. doi: 10.3389/fphys.2018.00516. eCollection 2018.
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 DDFs and 42 DNA DDFs 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.
在炎症条件下，炎症细胞会释放活性氧（ROS）和活性氮（RNS），从而导致DNA损伤。若DNA损伤未得到适当修复，就会导致基因突变和基因组不稳定。DNA损伤检查点因子（DDCF）和DNA损伤修复因子（DDRF）在维持基因组完整性方面发挥着至关重要的作用。然而，DDCF和DDRF在生理和病理条件下是如何被调节的，目前尚不完全清楚。我们通过实验数据库分析来确定26种DNA DDF和42种DNA DDF在21种人类组织和20种小鼠组织的生理/病理条件下的表达情况。我们有以下重要发现：（1）很少有DDCF和DDRF在组织中普遍表达，而许多则受到差异调节；（2）DDCF和DDRF的表达不仅在癌症中受到调节，在无菌性炎症疾病和代谢性疾病中也受到调节；（3）组织甲基化状态、促炎细胞因子、缺氧调节因子和组织血管生成潜力可以决定DDCF和DDRF的表达；（4）细胞内细胞器可以将应激信号传递到细胞核，这可能通过调节DDCF和DDRF的表达来调节细胞死亡。我们的结果表明，无菌性炎症疾病和癌症会增加基因组不稳定性，因此可被归类为具有高基因组风险的病理状态。我们还提出了一个新概念，即作为细胞传感器相互作用网络的一部分，DNA检查点和修复因子作为细胞内细胞器应激的核传感器。此外，这项工作将有助于识别代谢性疾病、炎症、组织损伤和癌症诊断及预后的新治疗靶点和新生物标志物。
