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
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated