標題另類DNA修復機制

被烷基化或脫氨基的DNA堿基，在一個保護基因組完整性、但同時又會干預癌癥烷基化療法的過程中被DNA糖基化酶（修復酶）清除。迄今所研究的DNA糖基化酶采用一個被修飾的堿基插入活性點的機制。

　　現在，最近發現的DNA糖基化酶AlkD的結構已被確定，并且也顯示了一個非常不同的機制。按這種機制，被修飾的堿基從一個“螺旋外”位置伸出，這個位置只使N3- 和N7-被烷基化的堿基發生解理。

　　DNA與AlkD的串聯HEAT重復段的相互作用使DNA 骨干發生扭曲，從而使“非Watson–Crick堿基對”能夠被檢測到。AlkD酶在細菌、古細菌、植物和真核生物中普遍存在，這便提出了一個有趣的問題：為什么消除基因組烷基化損傷會有另一種機制？

　　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.