FRA16D common chromosomal fragile site oxido-reductase (FOR/WWOX) protects against the effects of ionizing radiation in Drosophila.
Fragile sites are chromosomal structures that have been proposed to have a determining role in cancer-associated DNA instability. The human WWOX gene spans the FRA16D chromosomal fragile site, the common minimal region of homozygous deletion found in adenocarcinomas and three out of five translocation breakpoints in multiple myeloma. Transcripts from the alternatively spliced WWOX gene encode proteins with common N-terminal WW domains and variable homology to the oxidoreductase family of proteins. In this study, the Drosophila orthologue of the WWOX gene was identified and subjected to mutagenesis via homologous recombination. The resultant DmWWOX1 mutants were viable but exhibited an increased sensitivity to ionizing radiation. This radiation sensitivity was rescued by reintroduction and expression of either the wild-type Drosophila or human WWOX genes. Thus, the protective function of DmWWOX in response to irradiation in Drosophila is conserved with human WWOX (hWWOX). This is consistent with a protective role for hWWOX where aberrant expression, as a result of breakage at the associated fragile site, could contribute directly to cancer progression.
O'Keefe
Louise V
LV
ARC Special Research Centre for the Molecular Genetics of Development, The University of Adelaide, Adelaide, SA 5005, Australia.
Liu
Yinghong
Y
Perkins
Alison
A
Dayan
Sonia
S
Saint
Robert
R
Richards
Robert I
RI
D000818:Animals; D001483:Base Sequence; D043283:Chromosome Fragile Sites; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000528:radiation effects; D029721:Drosophila Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D004625:Embryo, Nonmammalian; D005786:Gene Expression Regulation; D006801:Humans; D007814:Larva; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects; D011839:Radiation, Ionizing; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase
D029721:Drosophila Proteins; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human