Wortmannin enhances the induction of micronuclei by low and
high LET radiation.
Oliveira NG, Castro M, Rodrigues AS, Goncalves IC, Gil OM, Fernandes AP,
Toscano-Rico JM, Rueff J.
Department of Genetics, Faculty of Medical Sciences, New University of Lisbon,
R. da Junqueira 96, P 1349-008 Lisbon, Portugal.
In mammalian cells, the repair of DNA double-strand breaks (DSBs) is mainly
mediated by DNA non-homologous end joining. DNA-dependent protein kinase (DNA-PK),
a nuclear serine-threonine kinase and a member of the phosphaditylinositol-3
kinase-related kinase family that is activated by DSBs, is a key component of
this pathway. Wortmannin (WM) is known to be an irreversible and potent
inhibitor of DNA-PK and has thus been proposed as an effective sensitizer for
ionizing radiation and for radiomimetic compounds. The present study, using the
cytokinesis block micronucleus assay, reports on the differential effect of WM
on the repair of the DNA damage induced by low LET ((60)Co gamma-radiation) and
high LET radiation by the boron neutron capture reaction (alpha and Li
particles) in V79 Chinese hamster cells. Significant increases in the number of
micronuclei per binucleated cell as well as in the frequency of micronucleated
binucleated cells were observed in the presence of different concentrations of
WM for high LET radiation from the boron neutron capture reaction. The increases
observed reached a maximum of approximately 2-fold in comparison with the
respective controls. WM, however, had a more pronounced effect on (60)Co
gamma-radiation-induced micronuclei, increasing the genotoxic damage from this
radiation by approximately 3- to 4-fold. These results are in general in
agreement with the concept that DSBs induced by high LET radiation are not a
more suitable substrate for the end joining processes mediated by DNA-PK, yet
they do not preclude a role for DNA-PK in high LET-induced damage repair.