DNA Checkpoint and Repair Factors Are Nuclear Sensors for Intracellular Organelle Stresses-Inflammations and Cancers Can Have High Genomic Risks.
DNA Checkpoint and Repair Factors Are Nuclear Sensors for Intracellular Organelle Stresses-Inflammations and Cancers Can Have High Genomic Risks.
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DNA 检查点和修复因子是细胞内细胞器应激的核传感器 - 炎症和癌症可能具有很高的基因组风险
DOI：
10.3389/fphys.2018.00516
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发表时间：
2018
影响因子：
4
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
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
在炎症条件下，炎症细胞释放活性氧 (ROS) 和活性氮 (RNS)，导致 DNA 损伤。如果修复不当，DNA 损伤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，DDCFs和DDRFs在生理和病理条件下如何调节尚不完全清楚。我们进行了实验数据库分析，以确定生理/病理条件下 21 个人类和 20 个小鼠组织中 26 个 DNA DDCF 和 42 个 DNA DDRF 的表达。我们得出以下重要发现：（1）很少有 DDCF 和 DDRF 在组织中普遍表达，而许多 DDCF 和 DDRF 受到差异调节。 (2)DDCFs和DDRFs的表达不仅在癌症中受到调节，而且在无菌性炎症性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能可以决定DDCFs和DDRFs的表达； (4)细胞内细胞器可将应激信号传递至细胞核，细胞核可能通过调节DDCF和DDRF的表达来调节细胞死亡。我们的结果表明，无菌性炎症性疾病和癌症会增加基因组的不稳定性，因此可以归类为具有高基因组风险的病理。我们还提出了一个新概念，即作为细胞传感器串扰网络的一部分，DNA 检查点和修复因子可作为细胞内细胞器应激的核传感器。此外，这项工作还将确定新的治疗靶点和新的生物标志物，用于代谢疾病、炎症、组织损伤和癌症的诊断和预后。
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.
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影响因子：
--
作者：
Guillaumet-Adkins A;Yañez Y;Peris-Diaz MD;Calabria I;Palanca-Ballester C;Sandoval J
通讯作者：
Sandoval J
影响因子：
28.5
作者：
Li X;Fang P;Mai J;Choi ET;Wang H;Yang XF
通讯作者：
Yang XF
影响因子：
3.5
作者：
Chung, Chan;Puthanveetil, Prasanth;Lieberman, Andrew P.
通讯作者：
Lieberman, Andrew P.
影响因子：
3.8
作者：
Li X;Fang P;Yang WY;Wang H;Yang X
通讯作者：
Yang X
影响因子：
4.8
作者：
Chen, Natalie C.;Yang, Fan;Wang, Hong
通讯作者：
Wang, Hong