Innate immune response orchestrates phosphoribosyl pyrophosphate synthetases to support DNA repair

Li, Rui; Li, Jingyi; Shao, Jichun; Lee, Jong-Ho; Qiu, Xuemei; Xiao, Yanxuan; Zhang, Bowen; Hao, Yilong; Li, Mi; Chen, Qianming

doi:10.1016/j.cmet.2021.07.009

Cited by 32 publications

(35 citation statements)

References 65 publications

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“…Isopropyl-β-D-thiogalactoside (IPTG) was used to induce the protein expression of rLYN. The rLYN protein was then purified by gel filtration chromatography (Chromdex 75 PG) and stored at -70 °C for use 40 , 41 .…”

Section: Methodsmentioning

confidence: 99%

Minocycline binds and inhibits LYN activity to prevent STAT3-meditated metastasis of colorectal cancer

Yang¹,

Yang²,

Liu³

et al. 2022

Int. J. Biol. Sci.

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Colorectal cancer (CRC) is one of the most common malignancies worldwide. Metastasis is a major cause of CRC recurrence and mortality. Several antibiotic drugs have been reported to exert potential anticancer activities, however, whether and how the tetracycline antibiotic minocycline exhibit tumor suppressive effect on CRC remains unknown. Here, we found that minocycline markedly inhibits the epithelial-mesenchymal transition (EMT) process and metastasis of CRC cells both in vitro and in vivo . Using chemical proteomics screening combined with docking analysis and site-directed mutagenesis, we identified LYN as a direct bind target of minocycline, and Ala255 of LYN is required for minocycline binding. Mechanistically, minocycline binding inactivates LYN, leading to STAT3 inactivation and EMT suppression, thereby inhibits CRC metastasis. Tissue microarray analysis further confirmed the clinical relevance of LYN-STAT3 axis in the EMT and progression of CRC. In addition to CRC, minocycline also significantly prevents EMT process and inhibits the metastasis of several other cancer types. Our findings elucidate the mechanism of action of minocycline for the inhibition of CRC metastasis by LYN binding, and suggest that repurposing minocycline may represent a promising strategy for the treatment of advanced CRC and other cancer types.

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Section: Methodsmentioning

confidence: 99%

Minocycline binds and inhibits LYN activity to prevent STAT3-meditated metastasis of colorectal cancer

Yang¹,

Yang²,

Liu³

et al. 2022

Int. J. Biol. Sci.

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“…Interestingly, the corresponding residue S 16 in murine PRPS1 and PRPS2 is a target of the ataxia-telangiectasia-mutated kinase (ATM) in response to ionizing radiation. Notably, the phosphorylation of residue T 228 in mPRPS1 and mPRPS2 is dependent on S 16 phosphorylation to preserve the high activity of mPRPS1 and mPRPS2, thus providing further evidence for the role of PRPP in the innate immune response [ 189 ].…”

Section: Retinal Dystrophymentioning

confidence: 99%

Contribution of Model Organisms to Investigating the Far-Reaching Consequences of PRPP Metabolism on Human Health and Well-Being

Ugbogu

Schweizer

2022

Cells

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Phosphoribosyl pyrophosphate synthetase (PRS EC 2.7.6.1) is a rate-limiting enzyme that irreversibly catalyzes the formation of phosphoribosyl pyrophosphate (PRPP) from ribose-5-phosphate and adenosine triphosphate (ATP). This key metabolite is required for the synthesis of purine and pyrimidine nucleotides, the two aromatic amino acids histidine and tryptophan, the cofactors nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+), all of which are essential for various life processes. Despite its ubiquity and essential nature across the plant and animal kingdoms, PRPP synthetase displays species-specific characteristics regarding the number of gene copies and architecture permitting interaction with other areas of cellular metabolism. The impact of mutated PRS genes in the model eukaryote Saccharomyces cerevisiae on cell signalling and metabolism may be relevant to the human neuropathies associated with PRPS mutations. Human PRPS1 and PRPS2 gene products are implicated in drug resistance associated with recurrent acute lymphoblastic leukaemia and progression of colorectal cancer and hepatocellular carcinoma. The investigation of PRPP metabolism in accepted model organisms, e.g., yeast and zebrafish, has the potential to reveal novel drug targets for treating at least some of the diseases, often characterized by overlapping symptoms, such as Arts syndrome and respiratory infections, and uncover the significance and relevance of human PRPS in disease diagnosis, management, and treatment.

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“…Then the increased deoxyribonucleotide will help for DNA repair. Nevertheless, it remains to be clarified how the cells respond to DNA damage via the cGAS-STING pathway under different contexts ( Kornberg et al, 1955 ; Hove-Jensen, 1988 ; Liu et al, 2021 ).…”

Section: The Impacts Of Nucleic Acid-sensing Pathways On Dna Repairmentioning

confidence: 99%

Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy

Xie

Luo

2022

Front. Cell Dev. Biol.

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The repair of DNA damage is a complex process, which helps to maintain genome fidelity, and the ability of cancer cells to repair therapeutically DNA damage induced by clinical treatments will affect the therapeutic efficacy. In the past decade, great success has been achieved by targeting the DNA repair network in tumors. Recent studies suggest that DNA damage impacts cellular innate and adaptive immune responses through nucleic acid-sensing pathways, which play essential roles in the efficacy of DNA repair targeted therapy. In this review, we summarize the current understanding of the molecular mechanism of innate immune response triggered by DNA damage through nucleic acid-sensing pathways, including DNA sensing via the cyclic GMP-AMP synthase (cGAS), Toll-like receptor 9 (TLR9), absent in melanoma 2 (AIM2), DNA-dependent protein kinase (DNA-PK), and Mre11-Rad50-Nbs1 complex (MRN) complex, and RNA sensing via the TLR3/7/8 and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). Furthermore, we will focus on the recent developments in the impacts of nucleic acid-sensing pathways on the DNA damage response (DDR). Elucidating the DDR-immune response interplay will be critical to harness immunomodulatory effects to improve the efficacy of antitumor immunity therapeutic strategies and build future therapeutic approaches.

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Innate immune response orchestrates phosphoribosyl pyrophosphate synthetases to support DNA repair

Cited by 32 publications

References 65 publications

Minocycline binds and inhibits LYN activity to prevent STAT3-meditated metastasis of colorectal cancer

Minocycline binds and inhibits LYN activity to prevent STAT3-meditated metastasis of colorectal cancer

Contribution of Model Organisms to Investigating the Far-Reaching Consequences of PRPP Metabolism on Human Health and Well-Being

Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy

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