TNF 受体超家族成员介导的非经典 NF-κB 通路
中文名称
通路描述
NF-κB 转录因子的激活对于 TNFRSF 成员介导的信号转导至关重要。NF-κB 靶基因的表达对于对感染微生物的先天免疫反应至关重要，同时也对于次级淋巴器官的正常发育和细胞分室化至关重要，这些器官对于协调适应性免疫反应必不可少。NF-κB 转录因子家族通过两条不同的途径被激活：经典途径涉及 NF-κB1 和非经典途径涉及 NF-κB2。与 NF-κB1 信号不同，后者可由多种受体激活，而 NF-κB2 途径通常由肿瘤坏死因子受体（TNF）超家族成员中的一小部分受体和配体对激活。这些成员包括 TNFR2（Rauert 等，2010）、B 细胞活化因子 TNF 受体家族成员（BAFFR，也称为 TNFRSF13C）（Kayagaki 等，2002）、CD40（也称为 TNFRSF5）（Coope 等，2002）、淋巴毒素β受体（LTBR，也称为 TNFRSF3）（Dejardin 等，2002）、核因子 kB 受体激活剂（RANK，也称为 TNFRSF11A）（Novack 等，2003）、CD27 和成纤维细胞生长因子诱导的立即早期反应蛋白 14（FN14，也称为 TNFRSF12A）等。这些受体各自介导非经典 NF-κB 的特异性生物学功能。这些非经典 NF-κB 刺激受体有一个共同点，即存在 TRAF 结合基序，该基序在配体结合时招募不同的 TNF 受体相关因子（TRAF）成员，特别是 TRAF2 和 TRAF3，到受体复合物中（Grech 等，2004，Bishop & Xie 2007）。这些 TRAF 成员的受体招募导致其降解，这是激活 NIK 和诱导 p100 加工的关键步骤（Sun 2011, 2012）。
英文描述
HDR through Single Strand Annealing (SSA) Homology directed repair (HDR) through single strand annealing (SSA), similar to HDR through homologous recombination repair (HRR), involves extensive resection of DNA double-strand break ends (DSBs), preceded by ATM activation and formation of the so-called ionizing radiation induced foci (IRIF) at DNA DSB sites. Following ATM activation and foci formation, the two-step resection is initiated by the MRN complex (MRE11A:RAD50:NBN) and RBBP8 (CtIP) associated with BRCA1:BARD1, and completed by EXO1 or DNA2 in cooperation with DNA helicases BLM, WRN and BRIP1 (BACH1) (Sartori et al. 2007, Yun and Hiom 2009, Eid et al. 2010, Nimonkar et al. 2011, Suhasini et al. 2011, Sturzenegger et al. 2014). Long 3'-ssDNA overhangs produced by extensive resection are coated by the RPA heterotrimer (RPA1:RPA2:RPA3), triggering ATR signaling. ATR signaling is needed for SSA, probably because of the related phosphorylation of RPA2 (Zou and Elledge 2003, Anantha et al. 2007, Liu et al. 2012).RAD52 is the key mediator of SSA. Activated ATM phosphorylates and activates ABL1, and activated ABL1 subsequently phosphorylates pre-formed RAD52 heptameric rings, increasing their affinity for ssDNA (Honda et al. 2011). Phosphorylated RAD52 binds phosphorylated RPA heterotrimers on 3'-ssDNA overhangs at resected DNA DSBs. RAD52 also binds RAD51 and prevents formation of invasive RAD51 nucleofilaments involved in HRR (Chen et al. 1999, Van Dyck et al. 1999, Parsons et al. 2000, Jackson et al. 2002, Singleton et al. 2002).RAD52 promotes annealing of two 3'-ssDNA overhangs when highly homologous directed repeats are present in both 3'-ssDNA overhangs. Nonhomologous regions lying 3' to the annealed repeats are displaced as 3'-flaps (Parsons et al. 2000, Van Dyck et al. 2001, Singleton et al. 2002, Stark et al. 2004, Mansour et al. 2008). The endonuclease complex composed of ERCC1 and ERCC4 (XPF) is subsequently recruited to SSA sites through direct interaction between RAD52 and ERCC4, leading to cleavage of 3' flaps (Motycka et al. 2004, Al-Minawi et al. 2008). The identity of a DNA ligase that closes the remaining single strand nicks (SSBs) to complete SSA-mediated repair is not known.SSA results in deletion of one of the annealed repeats and the intervening DNA sequence between the two annealed repeats and is thus mutagenic.
所含基因
37 个基因