The Drosophila werner exonuclease participates in an exonuclease-independent response to replication stress.

[werner syndrome]

Members of the RecQ family of helicases are known for their roles in DNA repair , replication , and recombination . Mutations in the human RecQ helicases , WRN and BLM , cause Werner and Bloom syndromes , which are diseases characterized by genome instability and an increased risk of cancer . While WRN contains both a helicase and an exonuclease domain , the Drosophila melanogaster homolog , WRNexo , contains only the exonuclease domain . Therefore the Drosophila model system provides a unique opportunity to study the exonuclease functions of WRN separate from the helicase . We created a null allele of WRNexo via imprecise P-element excision . The null WRNexo mutants are not sensitive to double -strand break-inducing reagents , suggesting that the exonuclease does not play a key role in homologous recombination-mediated repair of DSBs . However , WRNexo mutant embryos have a reduced hatching frequency and larvae are sensitive to the replication fork-stalling reagent , hydroxyurea (HU ), suggesting that WRNexo is important in responding to replication stress . The role of WRNexo in the HU-induced stress response is independent of Rad 51 . Interestingly , the hatching defect and HU sensitivity of WRNexo mutants do not occur in flies containing an exonuclease-dead copy of WRNexo , suggesting that the role of WRNexo in replication is independent of exonuclease activity . Additionally , WRNexo and Blm mutants exhibit similar sensitivity to HU and synthetic lethality in combination with mutations in structure-selective endonucleases . We propose that WRNexo and BLM interact to promote fork reversal following replication fork stalling and in their absence regressed forks are restarted through a Rad 51 -mediated process .

Diseases
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Diseases presenting "double-strand break-inducing reagents" symptom

werner syndrome

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