ABSTRACT
Transcription is extremely important for cellular processes but can be hindered by RNA polymerase II (RNAPII) pausing and stalling. Cockayne syndrome protein B (CSB) promotes the progression of paused RNAPII or initiates transcription-coupled nucleotide excision repair (TC-NER) to remove stalled RNAPII. However, the specific mechanism by which CSB initiates TC-NER upon damage remains unclear. In this study, we identified the indispensable role of the ARK2N-CK2 complex in the CSB-mediated initiation of TC-NER. The ARK2N-CK2 complex is recruited to damage sites through CSB and then phosphorylates CSB. Phosphorylation of CSB enhances its binding to stalled RNAPII, prolonging the association of CSB with chromatin and promoting CSA-mediated ubiquitination of stalled RNAPII. Consistent with this finding, Ark2n-/- mice exhibit a phenotype resembling Cockayne syndrome. These findings shed light on the pivotal role of the ARK2N-CK2 complex in governing the fate of RNAPII through CSB, bridging a critical gap necessary for initiating TC-NER.
Subject(s)
Cockayne Syndrome , DNA Helicases , DNA Repair Enzymes , DNA Repair , Poly-ADP-Ribose Binding Proteins , RNA Polymerase II , DNA Repair Enzymes/metabolism , DNA Repair Enzymes/genetics , RNA Polymerase II/metabolism , RNA Polymerase II/genetics , Poly-ADP-Ribose Binding Proteins/metabolism , Poly-ADP-Ribose Binding Proteins/genetics , Humans , Animals , Mice , DNA Helicases/metabolism , DNA Helicases/genetics , Cockayne Syndrome/genetics , Cockayne Syndrome/metabolism , Transcription, Genetic , Phosphorylation , Casein Kinase II/metabolism , Casein Kinase II/genetics , Mice, Knockout , DNA Damage , ATPases Associated with Diverse Cellular Activities/metabolism , ATPases Associated with Diverse Cellular Activities/genetics , Chromatin/metabolism , Ubiquitination , Excision RepairABSTRACT
Lung cancer is the deadliest and most aggressive malignancy in the world. Preventing cancer is crucial. Therefore, the new molecular targets have laid the foundation for molecular diagnosis and targeted therapy of lung cancer. PLA2G1B plays a key role in lipid metabolism and inflammation. PLA2G1B has selective substrate specificity. In this paper, the recombinant protein molecular structure of PLA2G1B was studied and novel therapeutic interventions were designed to disrupt PLA2G1B activity and impede tumor growth by targeting specific regions or residues in its structure. Construct protein-protein interaction networks and core genes using R's "STRING" program. LASSO, SVM-RFE and RF algorithms identified important genes associated with lung cancer. 282 deg were identified. Enrichment analysis showed that these genes were mainly related to adhesion and neuroactive ligand-receptor interaction pathways. PLA2G1B was subsequently identified as developing a preventative feature. GSEA showed that PLA2G1B is closely related to α-linolenic acid metabolism. Through the analysis of LASSO, SVM-RFE and RF algorithms, we found that PLA2G1B gene may be a preventive gene for lung cancer.