Abstract
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.
Highlights
Chronic inflammation is induced by damage associated molecular patterns (DAMPs) derived from endogenous metabolites
We hypothesized that the differences in stimulatory/suppressive environments in tissues may differentially modulate the expression of DNA damage checkpoint factors (DDCFs) in human tissues
For the first time we propose a novel concept that DDCFs and DNA damage repair factors (DDRFs) can act as nuclear sensors (Wang L. et al, 2016) for organelle stresses, which is a part of cellular sensor cross-talking network including classical DAMP receptors such as Toll-like receptors (Yang et al, 2008), caspase-1/Nod-like receptors and inflammasomes (Yin et al, 2013), conditional DAMPs receptors and our newly proposed homeostasis-associated molecular pattern receptors (Wang X. et al, 2016; Li et al, 2017a; Wang et al, 2017; Sun et al, 2018), and mitochondrial reactive oxygen species (ROS) (Li et al, 2013, 2016, 2017b; Cheng et al, 2017)
Summary
Chronic inflammation is induced by damage associated molecular patterns (DAMPs) derived from endogenous metabolites. Infectious agents-, and physiochemical factors-derived pathogen-associated molecular patterns (PAMPs) generated during tissue injury or microbial invasion promote inflammation via responsive innate immune system (Yang et al, 2008). DNA damage checkpoint factors (DDCFs) play a crucial role by arresting the cell cycle to allow the time to repair once a damage to DNA has taken place. The detailed characterization of DDCFs has classified as many as 26 human proteins into four categories including DNA damage sensors, mediators, transducers and effectors (Blanpain et al, 2011). How chronic inflammatory disorders such as metabolic cardiovascular diseases and cancers modulate the expression of these DDCFs and DDRFs remains poorly defined
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