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碱基切除修复

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碱基切除修复(BER)示意图

碱基切除修复(Base excision repair,BER)是细胞修复受损DNA的一种机制,主要用来修补大小较小、对DNA双股螺旋结构影响较小的损伤,包括去胺、被烷基化或氧化的碱基,如8-羟基鸟嘌呤英语8-Oxoguanine(8-oxoG)、7-甲基鸟苷黄嘌呤尿嘧啶[1][2]。大小较大、影响DNA结构较大的损伤(如紫外线造成的胸腺嘧啶二聚体)则是由核苷酸切除修复(NER)途径修补[3]细菌[4]古菌[5]与真核生物皆有碱基切除修复的机制。

BER的过程首先由DNA糖基酶英语DNA glycosylase移除损伤的碱基,形成AP位点,随后AP核酸内切酶英语AP endonuclease将此位点的磷酸二酯键切除,造成DNA单股断裂,接著再由DNA聚合酶合成缺失的碱基(与一般DNA复制的过程一样有DNA夹参与),可能仅合成单一缺失的碱基后由DNA连接酶完成修补(短补丁修复;short-patch BER),也可能合成2-10个核苷酸以取代下游的若干的核苷酸,由Flap核酸内切酶英语Flap endonuclease将旧有的核苷酸切除后,再由DNA连接酶完成修补(长补丁修复;long-patch BER)[6],两途径的选择由DNA损伤种类、细胞周期细胞分化状态与物种种类等因素决定[7]

DNA糖基酶的活性可能随老化而下降,使BER途径的效率降低[8]。另外BER途径的缺失与数种癌症有关[9][10]

参考文献

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  1. ^ Dasari, A.; Choi, J.-S.; Berdis, A.J. Chemotherapeutic intervention by inhibiting DNA polymerases. DNA Repair in Cancer Therapy (Second Edition). 2016: 179–224. doi:10.1016/B978-0-12-803582-5.00007-3. 
  2. ^ Jayanta Chaudhuri; Frederick W. Alt. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nature Reviews Immunology. 2004, 4 (7): 541–552. PMID 15229473. doi:10.1038/nri1395. 
  3. ^ Reardon JT, Sancar A. Purification and characterization of Escherichia coli and human nucleotide excision repair enzyme systems. Methods in Enzymology. 2006, 408: 189–213. ISBN 9780121828134. PMID 16793370. doi:10.1016/S0076-6879(06)08012-8. 
  4. ^ Wallace SS. Base excision repair: a critical player in many games.. DNA Repair (Amst). 2014, 19: 14–26. PMC 4100245可免费查阅. PMID 24780558. doi:10.1016/j.dnarep.2014.03.030. 
  5. ^ Grasso S, Tell G. Base excision repair in Archaea: back to the future in DNA repair.. DNA Repair (Amst). 2014, 21: 148–57. PMID 25012975. doi:10.1016/j.dnarep.2014.05.006. 
  6. ^ Liu Y, Prasad R, Beard WA, Kedar PS, Hou EW, Shock DD, Wilson SH. Coordination of Steps in Single-nucleotide Base Excision Repair Mediated by Apurinic/Apyrimidinic Endonuclease 1 and DNA Polymerase β. Journal of Biological Chemistry. 2007, 282 (18): 13532–13541. PMC 2366199可免费查阅. PMID 17355977. doi:10.1074/jbc.M611295200. 
  7. ^ Fortini P, Dogliotti E. Base damage and single-strand break repair: mechanisms and functional significance of short- and long-patch repair subpathways. DNA Repair. April 2007, 6 (4): 398–409. PMID 17129767. doi:10.1016/j.dnarep.2006.10.008. 
  8. ^ Atamna H, Cheung I, Ames BN. A method for detecting abasic sites in living cells: age-dependent changes in base excision repair. Proc. Natl. Acad. Sci. U.S.A. 2000, 97 (2): 686–91. PMC 15391可免费查阅. PMID 10639140. doi:10.1073/pnas.97.2.686. 
  9. ^ Chaisaingmongkol J, Popanda O, Warta R, Dyckhoff G, Herpel E, Geiselhart L, Claus R, Lasitschka F, Campos B, Oakes CC, Bermejo JL, Herold-Mende C, Plass C, Schmezer P. Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma. Oncogene. 2012, 31 (49): 5108–16. PMID 22286769. doi:10.1038/onc.2011.660. 
  10. ^ Farrington, S. M.; Tenesa, A; Barnetson, R; Wiltshire, A; Prendergast, J; Porteous, M; Campbell, H; Dunlop, M. G. Germline susceptibility to colorectal cancer due to base-excision repair gene defects. The American Journal of Human Genetics. 2005, 77 (1): 112–9. PMC 1226182可免费查阅. PMID 15931596. doi:10.1086/431213.