DNA双链断裂末端的加工
中文名称
通路描述
同源定向修复（HDR）通过同源重组（HRR）或单链退火（SSA）需要DNA双链断裂（DSB）末端的广泛切除（Thompson and Limoli 2003, Ciccia and Elledge 2010）。切除过程分为两步，由MRN复合物（MRE11A:RAD50:NBN）和RBBP8（CtIP）与BRCA1结合启动。该步骤受CDK2和CCNA（周期素A）复合物调控，确保在细胞周期的S期和G2期（姐妹染色单体可用时）启动HRR。初始切除还受ATM介导的RBBP8磷酸化和CHEK2介导的BRCA1磷酸化调控（Chen et al. 2008, Yun and Hiom 2009, Buis et al. 2012, Wang et al. 2013, Davies et al. 2015, Parameswaran et al. 2015）。初始切除后，DNA核酸酶EXO1和/或DNA2执行长距离切除，由DNA解旋酶BLM或WRN以及BRIP1（BACH1）促进（Chen et al. 2008, Nimonkar et al. 2011, Sturzenegger et al. 2014, Suhasini et al. 2011）。产生的长3'-ssDNA突出端被RPA异三聚体（RPA1:RPA2:RPA3）覆盖，招募ATR:ATRIP复合物到DNA DSB上，并与RAD17:RFC和RAD9:HUS1:RAD1复合物以及TOPBP1和RHNO1协同作用，激活ATR信号。激活的ATR磷酸化RPA2并激活CHEK1（Cotta-Ramusino et al. 2011），两者都是HRR和SSA后续步骤的必要前提。
英文描述
Aflatoxin activation and detoxification Aflatoxins are among the principal mycotoxins produced as secondary metabolites by the molds Aspergillus flavus and Aspergillus parasiticus that contaminate economically important food and feed crops (Wild & Turner 2002). Aflatoxin B1 (AFB1) is the most potent naturally occurring carcinogen known and is also an immunosuppressant. It is a potent hepatocarcinogenic agent in many species, and has been implicated in the etiology of human hepatocellular carcinoma. Poultry, especially turkeys, are extremely sensitive to the toxic and carcinogenic action of AFB1 present in animal feed, resulting in multi-million dollar losses to the industry. Discerning the biochemical and molecular mechanisms of this extreme sensitivity of poultry to AFB1 will help with the development of new strategies to increase aflatoxin resistance (Rawal et al. 2010, Diaz & Murcia 2011).
AFB1 has one major genotoxic metabolic fate, conversion to AFXBO, and several others that are less mutagenic but that can still be quite toxic. AFB1 can be oxidised to the toxic AFB1 exo 8,9 epoxide (AFXBO) product by several cytochrome P450 enzymes, especially P450 3A4 in the liver. This 8,9 epoxide can react with the N7 atom of a guanyl base of DNA to produce adducts by intercalating between DNA base pairs. The exo epoxide is unstable in solution, however, and can react spontaneously to form a diol that is no longer reactive with DNA. The diol product in turn undergoes base-catalysed rearrangement to a dialdehyde that can react with protein lysine residues. AFB1 can also be metabolised to products (AFQ1, AFM1, AFM1E) which have far less genotoxic consequences than AFB1. The main route of detoxification of AFB1 is conjugation of its reactive 8,9-epoxide form with glutathione (GSH). This reaction is carried out by trimeric glutathione transferases (GSTs), providing a chemoprotective mechanism against toxicity. Glutathione conjugates are usually excreted as mercapturic acids in urine (Guengerich et al. 1998, Hamid et al. 2013). The main metabolic routes of aflatoxin in humans are described here.
AFB1 has one major genotoxic metabolic fate, conversion to AFXBO, and several others that are less mutagenic but that can still be quite toxic. AFB1 can be oxidised to the toxic AFB1 exo 8,9 epoxide (AFXBO) product by several cytochrome P450 enzymes, especially P450 3A4 in the liver. This 8,9 epoxide can react with the N7 atom of a guanyl base of DNA to produce adducts by intercalating between DNA base pairs. The exo epoxide is unstable in solution, however, and can react spontaneously to form a diol that is no longer reactive with DNA. The diol product in turn undergoes base-catalysed rearrangement to a dialdehyde that can react with protein lysine residues. AFB1 can also be metabolised to products (AFQ1, AFM1, AFM1E) which have far less genotoxic consequences than AFB1. The main route of detoxification of AFB1 is conjugation of its reactive 8,9-epoxide form with glutathione (GSH). This reaction is carried out by trimeric glutathione transferases (GSTs), providing a chemoprotective mechanism against toxicity. Glutathione conjugates are usually excreted as mercapturic acids in urine (Guengerich et al. 1998, Hamid et al. 2013). The main metabolic routes of aflatoxin in humans are described here.
所含基因
19 个基因