The Drosophila orthologue of progeroid human WRN exonuclease, DmWRNexo, cleaves replication substrates but is inhibited by uracil or abasic sites : analysis of DmWRNexo activity in vitro.

[werner syndrome]

Werner syndrome (WS ) is a rare late-onset premature ageing disease showing many of the phenotypes associated with normal ageing , and provides one of the best models for investigating cellular pathways that lead to normal ageing . WS is caused by mutation of WRN , which encodes a multifunctional DNA replication and repair helicase /exonuclease . To investigate the role of WRN protein 's unique exonuclease domain , we have recently identified DmWRNexo , the fly orthologue of the exonuclease domain of human WRN . Here , we fully characterise DmWRNexo exonuclease activity in vitro , confirming 3 '-5 ' polarity , demonstrating a requirement for Mg (2 +), inhibition by ATP , and an ability to degrade both single -stranded DNA and duplex DNA substrates with 3 ' or 5 ' overhangs , or bubble structures , but with no activity on blunt ended DNA duplexes . We report a novel active site mutation that ablates enzyme activity . Lesional substrates containing uracil are partially cleaved by DmWRNexo , but the enzyme pauses on such substrates and is inhibited by abasic sites . These strong biochemical similarities to human WRN suggest that Drosophila can provide a valuable experimental system for analysing the importance of WRN exonuclease in cell and organismal ageing .

Diseases
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Diseases presenting "active site mutation" symptom

werner syndrome

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