被烷基化或脫氨基的DNA堿基，在一個(gè)保護(hù)基因組完整性、但同時(shí)又會干預(yù)癌癥烷基*法的過程中被DNA糖基化酶（修復(fù)酶）清除。迄今所研究的DNA糖基化酶采用一個(gè)被修飾的堿基插入活性點(diǎn)的機(jī)制。
現(xiàn)在，zui近發(fā)現(xiàn)的DNA糖基化酶AlkD的結(jié)構(gòu)已被確定，并且也顯示了一個(gè)非常不同的機(jī)制。按這種機(jī)制，被修飾的堿基從一個(gè)“螺旋外”位置伸出，這個(gè)位置只使N3- 和N7-被烷基化的堿基發(fā)生解理。
DNA與AlkD的串聯(lián)HEAT重復(fù)段的相互作用使DNA 骨干發(fā)生扭曲，從而使“非Watson–Crick堿基對”能夠被檢測到。AlkD酶在細(xì)菌、古細(xì)菌、植物和真核生物中普遍存在，這便提出了一個(gè)有趣的問題：為什么消除基因組烷基化損傷會有另一種機(jī)制？
英文摘要：
Nature doi:10.1038/nature09428
An unprecedented nucleic acid capture mechanism for excision of DNA damage
Emily H. Rubinson,A. S. Prakasha Gowda,Thomas E. Spratt,Barry Gold& Brandt F. Eichman
DNA glycosylases that remove alkylated and deaminated purine nucleobases are essential DNA repair enzymes that protect the genome, and at the same time confound cancer alkylation therapy, by excising cytotoxic N3-methyladenine bases formed by DNA-targeting anticancer compounds. The basis for glycosylase specificity towards N3- and N7-alkylpurines is believed to result from intrinsic instability of the modified bases and not from direct enzyme functional group chemistry. Here we present crystal structures of the recently discovered Bacillus cereus AlkD glycosylase in complex with DNAs containing alkylated, mismatched and abasic nucleotides. Unlike other glycosylases, AlkD captures the extrahelical lesion in a solvent-exposed orientation, providing an illustration for how hydrolysis of N3- and N7-alkylated bases may be facilitated by increased lifetime out of the DNA helix. The structures and supporting biochemical analysis of base flipping and catalysis reveal how the HEAT repeats of AlkD distort the DNA backbone to detect non-Watson–Crick base pairs without duplex intercalation.
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