Prasad R, Beard W A, Batra V K, Liu Y, Shock D D, Wilson S H
Laboratory of Structural Biology, National Institutes of Health, NIEHS, 111 T. W. Alexander Drive, PO Box 12233, MD F1-12, Research Triangle Park, North Carolina 27709, USA.
Mol Biol (Mosk). 2011 Jul-Aug;45(4):586-600.
The current "working model" for mammalian base excision repair involves two sub-pathways termed single-nucleotide base excision repair and long patch base excision repair that are distinguished by their repair patch sizes and the enzymes/co-factors involved. These base excision repair sub-pathways are designed to sequester the various DNA intermediates, passing them along from one step to the next without allowing these toxic molecules to trigger cell cycle arrest, necrotic cell death, or apoptosis. Although a variety of DNA-protein and protein-protein interactions are known for the base excision repair intermediates and enzymes/co-factors, the molecular mechanisms accounting for step-to-step coordination are not well understood. In this review, we explore the question of whether there is an actual step-to-step "hand-off" of the DNA intermediates during base excision repair in vitro. The results show that when base excision repair enzymes are pre-bound to the initial single-nucleotide base excision repair intermediate, the DNA is channeled from apurinic/apyrimidinic endonuclease 1 to DNA polymerase beta and then to DNA ligase. In the long patch base excision repair sub-pathway, where the 5'-end of the incised strand is blocked, the intermediate after polymerase beta gap filling is not channeled from polymerase beta to the subsequent enzyme, flap endonuclease 1. Instead, flap endonuclease 1 must recognize and bind to the intermediate in competition with other molecules.
目前哺乳动物碱基切除修复的“工作模式”涉及两个子途径，即单核苷酸碱基切除修复和长片段碱基切除修复，它们通过修复片段大小以及所涉及的酶/辅助因子来区分。这些碱基切除修复子途径旨在隔离各种DNA中间体，使其从一个步骤传递到下一个步骤，而不让这些有毒分子触发细胞周期停滞、坏死性细胞死亡或凋亡。尽管已知碱基切除修复中间体与酶/辅助因子之间存在多种DNA-蛋白质和蛋白质-蛋白质相互作用，但对于逐步协调的分子机制仍了解不足。在本综述中，我们探讨了在体外碱基切除修复过程中，DNA中间体是否存在实际的逐步“交接”问题。结果表明，当碱基切除修复酶预先结合到初始单核苷酸碱基切除修复中间体上时，DNA会从脱嘌呤/脱嘧啶内切酶1传递至DNA聚合酶β，然后再传递至DNA连接酶。在长片段碱基切除修复子途径中，切口链的5'端被阻断，聚合酶β填补缺口后的中间体不会从聚合酶β传递至后续酶——瓣状核酸内切酶1。相反，瓣状核酸内切酶1必须在与其他分子竞争的情况下识别并结合该中间体。
