Carcinogenesis, Vol 19, 591-596, Copyright © 1998 by Oxford University Press
M Savio, LA Stivala, L Bianchi, V Vannini and E Prosperi
The involvement of the proliferating cell nuclear antigen (PCNA) in the
process of DNA repair induced by alkylating agents or by oxidative damage
was investigated in human quiescent fibroblasts by immunofluorescence and
flow cytometry. Transition from soluble to the DNA-bound form of PCNA, was
taken as the parameter to determine its involvement in repair DNA
synthesis. Treatment with the alkylating agents methylmethane sulfonate and
N-methyl-N'-nitro-N-nitrosoguanidine resulted in the rapid and
dose-dependent increase in the nuclear binding of PCNA. Similar results
were obtained with compounds such as hydrogen peroxide or tert-butyl
hydroperoxide, which are known to induce oxidative DNA damage. Tert-butyl
hydroperoxide may also generate malondialdehyde through a reaction of lipid
peroxidation. This mutagenic and carcinogenic product has been previously
shown to form adducts with DNA. Therefore, the possibility that tert-butyl
hydroperoxide could induce DNA damage through this pathway was investigated
by incubating cells directly in the presence of malondialdehyde. Such
treatment resulted in an increase in immunofluorescence associated with
nuclear-bound PCNA. The ability of oxidative and alkylating agents to
induce the nuclear binding of PCNA was also assessed in proliferating
cells. In these conditions, treatment with hydrogen peroxide or
methylmethane sulfonate, resulted in an increase in nuclear-bound PCNA in
the G1 and in the G2 + M compartments, but not in S phase. At longer times
after treatment, PCNA immunostaining was reduced to basal levels, while an
increase in nuclear binding of p21(waf1/cip1) protein was found in
concomitance with cell-cycle arrest. These results indicate that agents
inducing DNA base alterations in vivo, promote the nuclear binding of PCNA.
These lines of evidence support the role of a PCNA-dependent reaction in
the base excision repair system.
ARTICLES
Involvement of the proliferating cell nuclear antigen (PCNA) in DNA repair induced by alkylating agents and oxidative damage in human fibroblasts
Istituto di Patologia Generale, Universita di Pavia, Italy.
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