DNA双链断裂处招募和ATM介导的修复及信号蛋白磷酸化
中文名称
通路描述
ATM磷酸化参与DNA损伤检查点和修复的多种蛋白，从而触发并协调DNA双链断裂（DSB）修复蛋白在核小体聚集区（IRIF）的积累。虽然IRIF包含位于DSB位点数千碱基处的染色质区域，但本Reactome通路代表简化模型，描述了发生在DSB末端附近的反应事件。在ATM信号下，定位到核小体聚集区的蛋白协同保留在DSB位点，形成正反馈回路并放大DNA损伤反应。ATM磷酸化MRN复合物（NBN）的NBN亚基，以及H2AFX在丝氨酸139位点，产生含γ-H2AFX的核小体。H2AFX在基础条件下在酪氨酸142位点磷酸化。ATM介导的H2AFX在丝氨酸139位点的磷酸化后，需由EYA家族磷酸酶去磷酸化酪氨酸142位点，以便DNA修复进行并避免由DNA DSB诱导的凋亡。γ-H2AFX招募MDC1到DNA DSB上。ATM磷酸化MDC1后，MRN复合物、γ-H2AFX核小体和MDC1作为核小体聚集体的核心，并作为招募参与DNA损伤信号和修复的其他蛋白的平台。RNF8泛素连接酶结合磷酸化的MDC1，与HERC2和RNF168合作泛素化H2AFX、去甲基化酶KDM4A和KDM4B。泛素化的γ-H2AFX招募UIMC1（RAP80），促进BRCA1-A复合物在DNA DSB上的组装。BRCA1-A复合物由RAP80、FAM175A（Abraxas）、BRCA1:BARD1异二聚体、BRCC3（BRCC36）、BRE（BRCC45）和BABAM1（MERIT40, NBA1）组成。泛素化KDM4A和KDM4B的降解允许TP53BP1（53BP1）在DNA DSB位点与H4K20Me2标记的组蛋白H4二聚体结合，由WHSC1介导。一旦招募到DNA DSB上，BRCA1:BARD1异二聚体和TP53BP1均被ATM磷酸化，触发CHEK2（Chk2, Cds1）的招募和激活。根据细胞周期阶段，BRCA1和TP53BP1竞争性地促进同源定向修复（HDR）或非同源末端连接（NHEJ）的DNA DSB修复。HDR通过同源重组修复（HRR）或单链退火（SSA）被BRCA1促进，与RBBP8（CtIP）结合；NHEJ由TP53BP1促进，与RIF1结合。
英文描述
Amplification and propagation of coagulation cascade The amplification and propagation phases of coagulation are characterized by the production of large amounts of activated coagulation factors, accompanied by platelet activation. This leads to a substantial burst of thrombin generation on the surfaces of platelet membranes (reviewed by Hoffman M & Monroe DM, 2001; Hoffman M, 2003; Smith SA, 2009; O'Donnell JS et al., 2019; Preston RJS et al., 2019).During the amplification phase, a small amount of thrombin (FIIa) produced during the tissue factor (TF)-mediated initiation phase facilitates further coagulation. On the platelet surface, thrombin activates coagulation factors XI (FXI), VIII (FVIII), and V (FV). Activated FXI (FXIa) converts factor IX (FIX) into its active form (FIXa), which then associates with the cofactor FVIIIa. The resulting FIXa:FVIIIa complex, known as the tenase complex, activates factor X (FX) to FXa. FXa subsequently binds to FVa, forming the FXa:FVa complex, also called prothrombinase. The prothrombinase complex converts prothrombin to thrombin, which in turn cleaves and activates additional FXI, FVIII, and FV, creating positive feedback loops (O'Donnell JS et al., 2019; Preston RJS et al., 2019).Thrombin also interacts with platelet surface receptors, such as protease-activated receptors (PARs), contributing to platelet activation, degranulation, and the recruitment of additional platelets to the injury site. Activated platelets aggregate, forming a platelet plug (Swieringa F et al., 2018; Sang Y et al., 2021). Procoagulant platelets further release clotting factors and expose phosphatidylserine (PS) on their cell membranes, providing surfaces for coagulation factors and promoting the assembly of the tenase (FIXa:FVIIIa) and prothrombinase (FXa:FVa) complexes (Lentz BR 2003; Swieringa F et al., 2018; Sang Y et al., 2021; Majumder R 2022). This generates large amounts of thrombin through FXa:FVa-catalyzed two-site cleavage of prothrombin (FII). While thrombin generation primarily occurs on the surfaces of activated platelets, other PS-bearing cells, such as leukocytes and endothelial cells, may also contribute (Zhang Y et al., 2016; Tong D et al., 2018).Thrombin produced during the amplification and propagation phases converts soluble fibrinogen into fibrin monomers, which polymerize to form insoluble fibrin fibers. Thrombin also activates FXIIIa, which cross-links fibrin fibers, stabilizing the thrombus (reviewed by Hoffman M & Monroe DM, 2001; Hoffman M, 2003; Roberts HR et al., 2006; Smith SA, 2009; O'Donnell JS et al., 2019; Preston RJS et al., 2019).
所含基因
15 个基因