Fanconi 贫血通路
中文名称
通路描述
Fanconi 贫血（FA）是一种基因组不稳定性遗传病，特征为先天性骨骼缺陷、再生障碍性贫血、白血病易感性以及对 DNA 损伤剂的细胞敏感性。患者被分类为至少 15 种互补组（FA-A 至 FA-P）。这些互补组对应于 FANCA、FANCB、FANCC、FANCD1/BRCA2、FANCD2、FANCE、FANCF、FANCG、FANCJ/BRIP1、FANCL、FANCM、FANCN/PALB2、FANCO/RAD51C 和 FANCP/SLX4 基因。其中，FANCA、FANCB、FANCC、FANCE、FANCF、FANCG、FANCL 和 FANCM 与 FAAP24、FAAP100、FAAP20、APITD1 和 STRA1 形成核内复合物，称为 FA 核心复合物。FA 核心复合物是一种 E3 泛素连接酶，可识别并响应由双链交联（ICLs）引起的 DNA 损伤，触发 FANCD2 和 FANCI 的单泛素化，从而启动 ICL-DNA 的修复。FANCD2 和 FANCI 形成复合物，彼此依赖进行单泛素化。在 DNA 损伤和 S 期期间，FANCD2 定位到核内斑点，并与同源重组修复蛋白如 BRCA1 和 RAD51 共定位。FA 通路通过 FANCD2 和 FANCI 的泛素化和磷酸化进行调控。ATR 依赖性磷酸化促进 FANCD2 的单泛素化，刺激 FA 通路（Cohn and D'Andrea 2008, Wang 2007）。USP1 和 WDR48（UAF1）复合物负责 FANCD2 的去泛素化，负向调节 FA 通路（Cohn et al. 2007）。单泛素化的 FANCD2 招募 DNA 核酸酶，包括 SLX4（FANCP）和 FAN1，使 ICL 从两条共价连接的 DNA 链中的一条解离。DNA 聚合酶 nu（POLN）利用解离的 ICL 作为模板进行跨损伤 DNA 合成，从而绕过未解离的 ICL。随后，未解离的 ICL 通过核苷酸切除修复（NER）从 DNA 中移除。解离过程中停滞的复制叉切口产生双链断裂（DSB）。DSB 通过同源重组修复（HRR）修复，涉及 FA 基因 BRCA2（FANCD1）、PALB2（FANCN）和 BRIP1（FANCJ）（综述：Deans and West 2011, Kottemann and Smogorzewska 2013）。BRCA2、PALB2 或 BRIP1 的纯合突变导致 Fanconi 贫血，而杂合突变则使携带者主要易患乳腺癌和卵巢癌。BRCA2、PALB2 和 BRIP1 在 DNA 修复中的已知功能依赖于 BRCA1，但尚未确定这些蛋白在 Fanconi 贫血通路中是否还有不依赖 BRCA1 的其他作用。杂合 BRCA1 突变使携带者易患乳腺癌和卵巢癌，且具有高度渗透率。BRCA1 功能的完全丧失在胚胎期是致死的。最近报道，通过减少 BRCA1 BRCT 域蛋白结合能力的杂合基因突变导致 FA 样综合征，BRCA1 因此被指定为 FANCS 基因（Jiang and Greenberg 2015）。FA 通路参与修复由正常细胞代谢产物产生的内源性突变剂引起的 DNA ICLs，例如含醛基化合物。FANCD2 缺陷小鼠中 ALDH2 基因（醛脱氢酶基因）的破坏导致严重的发育缺陷、早期致死和白血病易感性。此外，双突变小鼠对乙醇摄入异常敏感，因为乙醇代谢产生积累的醛类物质（Langevin et al. 2011）。
英文描述
Pre-NOTCH Processing in Golgi NOTCH undergoes final posttranslational processing in the Golgi apparatus (Lardelli et al. 1994, Blaumueller et al. 1997, Weinmaster et al. 1991, Weinmaster et al. 1992, Uyttendaele et al. 1996). Movement of NOTCH precursors from the endoplasmic reticulum to Golgi is controlled by SEL1L protein, a homolog of C. elegans sel-1. SEL1L localizes to the endoplasmic reticulum membrane and prevents translocation of misfolded proteins, therefore serving as a quality control check (Li et al. 2010, Sundaram et al. 1993, Francisco et al. 2010). Similarly, C. elegans sel-9 and its mammalian homolog TMED2 are Golgi membrane proteins that participate in quality control of proteins transported from Golgi to the plasma membrane. Translocation of a mutant C. elegans NOTCH homolog lin-12 from the Golgi to the plasma membrane is negatively regulated by sel-9 (Wen et al. 1999). A GTPase RAB6 positively controls NOTCH trafficking through Golgi (Purcell et al. 1999).
Processing of mammalian NOTCH precursors in the Golgi typically involves the cleavage by FURIN convertase. Pre-NOTCH is a ~300 kDa protein, and cleavage by FURIN produces two fragments with approximate sizes of 110 kDa and 180 kDa. The 110 kDa fragment contains the transmembrane and intracellular domains of NOTCH and is known as NTM or NTMICD. The 189 kDa fragment contains NOTCH extracellular sequence and is known as NEC or NECD. The NTM and NEC fragments heterodimerize (Blaumueller et al. 1997, Logeat et al. 1998, Chan et al. 1998) and are held together by disulfide bonds and calcium ions (Rand et al. 2000, Gordon et al. 2009).
An optional step in Pre-NOTCH processing in the Golgi is modification by fringe enzymes. Fringe enzymes are glycosyl transferases that initiate elongation of O-linked fucose on fucosylated peptides by addition of a beta 1,3 N-acetylglucosaminyl group, resulting in formation of disaccharide chains on NOTCH EGF repeats (GlcNAc-bet1,3-fucitol). Three fringe enzymes are known in mammals: LFNG (lunatic fringe), MFNG (manic fringe) and RFNG (radical fringe). LFNG shows the highest catalytic activity in modifying NOTCH (Bruckner et al. 2000, Moloney et al. 2000). Fringe-created disaccharide chains on NOTCH EGF repeats are further extended by B4GALT1 (beta-1,4-galactosyltransferase 1), which adds galactose to the N-acetylglucosaminyl group, resulting in formation of trisaccharide Gal-beta1,4-GlcNAc-beta1,3-fucitol chains (Moloney et al. 2000, Chen et al. 2001). Formation of trisaccharide chains is the minimum requirement for fringe-mediated modulation of NOTCH signaling, although fringe-modified NOTCH expressed on the cell surface predominantly contains tetrasaccharide chains on EGF repeats. The tetrasaccharide chains are formed by sialyltransferase(s) that add sialic acid to galactose, resulting in formation of Sia-alpha2,3-Gal-beta1,4-GlcNAc-beta1,3-fucitol (Moloney et al. 2000). Three known Golgi membrane sialyltransferases could be performing this function: ST3GAL3, ST3GAL4 and ST3GAL6 (Harduin-Lepers et al. 2001). The modification of NOTCH by fringe enzymes modulates NOTCH-signaling by increasing the affinity of NOTCH receptors for delta-like ligands, DLL1 and DLL4, while decreasing affinity for jagged ligands, JAG1 and JAG2.
Processing of mammalian NOTCH precursors in the Golgi typically involves the cleavage by FURIN convertase. Pre-NOTCH is a ~300 kDa protein, and cleavage by FURIN produces two fragments with approximate sizes of 110 kDa and 180 kDa. The 110 kDa fragment contains the transmembrane and intracellular domains of NOTCH and is known as NTM or NTMICD. The 189 kDa fragment contains NOTCH extracellular sequence and is known as NEC or NECD. The NTM and NEC fragments heterodimerize (Blaumueller et al. 1997, Logeat et al. 1998, Chan et al. 1998) and are held together by disulfide bonds and calcium ions (Rand et al. 2000, Gordon et al. 2009).
An optional step in Pre-NOTCH processing in the Golgi is modification by fringe enzymes. Fringe enzymes are glycosyl transferases that initiate elongation of O-linked fucose on fucosylated peptides by addition of a beta 1,3 N-acetylglucosaminyl group, resulting in formation of disaccharide chains on NOTCH EGF repeats (GlcNAc-bet1,3-fucitol). Three fringe enzymes are known in mammals: LFNG (lunatic fringe), MFNG (manic fringe) and RFNG (radical fringe). LFNG shows the highest catalytic activity in modifying NOTCH (Bruckner et al. 2000, Moloney et al. 2000). Fringe-created disaccharide chains on NOTCH EGF repeats are further extended by B4GALT1 (beta-1,4-galactosyltransferase 1), which adds galactose to the N-acetylglucosaminyl group, resulting in formation of trisaccharide Gal-beta1,4-GlcNAc-beta1,3-fucitol chains (Moloney et al. 2000, Chen et al. 2001). Formation of trisaccharide chains is the minimum requirement for fringe-mediated modulation of NOTCH signaling, although fringe-modified NOTCH expressed on the cell surface predominantly contains tetrasaccharide chains on EGF repeats. The tetrasaccharide chains are formed by sialyltransferase(s) that add sialic acid to galactose, resulting in formation of Sia-alpha2,3-Gal-beta1,4-GlcNAc-beta1,3-fucitol (Moloney et al. 2000). Three known Golgi membrane sialyltransferases could be performing this function: ST3GAL3, ST3GAL4 and ST3GAL6 (Harduin-Lepers et al. 2001). The modification of NOTCH by fringe enzymes modulates NOTCH-signaling by increasing the affinity of NOTCH receptors for delta-like ligands, DLL1 and DLL4, while decreasing affinity for jagged ligands, JAG1 and JAG2.
所含基因
19 个基因