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SIMM obtained two crystal structures of human ALKBH2 mutant bound to duplex DNA
Update time: 2014-07-20
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Cellular DNA at many different sites can be modified by endogenous and environmental methylating agents, giving rise to mutagenic and lethal lesions.In order to maintain genome integrity, multiple mechanisms for conserved DNA methylation damage repair have been evolved, which are initiated by three types of enzymes, including DNA glycosylase, DNA methyltransferase and AlkB-mediated direct oxidative demethylase. E. coli AlkB is Fe2+and 2-oxoglutarate dependent dioxygenase, which oxidizes the target methyl group and releases it as formaldehyde.

As a functional human homologue of AlkB, Mammalian AlkB homologue 2 (ALKBH2) has been detected in more than ten different tissues. ALKBH2 is the primary housekeeping DNA demethylase, effectively repairing endogenously formed methylated lesions in double-stranded DNA. Prof. Yang Caiguang group’s previous studies demonstrated that a hydrophobic β-hairpin motif of ALKBH2 could play crucial roles in base-pair stability interrogation and damaged base flipping.

Using chemical cross-linking strategy, two crystal structures of human ALKBH2 mutant bound to duplex DNA was obtained. The structural analysis suggests that the β-hairpin motif is flexible in conformation and is likely to slid e along the DNA duplex in local regions to search for damaged base. This study provides a new mechanistic insight into DNA damage detection by ALKBH2.

This work has been published on Science China Chemistry (Chen B E, Gan J H, Yang C G. The complex structures of ALKBH2 mutants cross-linked to dsDNA reveal the conformational swing of β-hairpin[J]. Science China Chemistry, 2014, 57(2): 307-313.)

                        

Figure 1. Scheme of distal cross-linking. ALKBH2 G169C mutation wasintroduced as the linkage site. A disulphide-tethered modified cytosine (C*)was incorporated into the synthesized DNA probe. Under equilibriumconditions, ALKBH2 locates to C*, and forms favorable complexesthrough a covalent disulphide cross-linking between C169 and C*.(Image by SIMM)

 
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