Poly (ADP-ribose) polymerase-1 deficiency does not affect ethylnitrosourea mutagenicity in liver and testis of lacZ transgenic mice.
Poly (ADP-ribose) polymerase-1 (Parp1) has been implicated in DNA base excision repair, single- and double-strand break repair pathways, as well as in cell death by apoptosis or necrosis. We used Parp1(-/-) lacZ plasmid-based transgenic mice to investigate whether Parp1 deficiency influences the in vivo mutagenic and clastogenic response to the alkylating agent N-ethyl-N-Nitrosourea (ENU) in somatic and germ-cell tissues. The comparison of the lacZ mutant frequencies (MFs) between Parp1(+/+) and Parp1(-/-) mice showed that the ablation of Parp1 does not affect the spontaneous or ENU-induced MFs in liver and testis. In addition, the spectrum of the ENU-induced mutations was not dependent on the Parp1 status, given that similar spectra, consisting mostly of point mutations and a small fraction of deletions/insertions, wereobserved in organs of both Parp1(-/-) and Parp1(+/+) mice. Sequencing of point mutations revealed a consistent significant increase in A:T --> T:A base substitutions, typically induced by ENU. Overall, we observed that neither the frequency nor the spectrum of ENU-induced mutations demonstrated a specificity that could be attributed to the Parp1 impairment in mice organs. The analysis of micronucleus frequency in peripheral blood reticulocytes showed that ENU was clastogenic in both Parp1(-/-) and Parp1(+/+) mice and had a strong cytotoxic effect in Parp1(-/-) mice only. The present data suggest that, at a whole-organism level, Parp1-independent repair mechanisms may be operative in the removal of ENU-induced DNA lesions or that highly damaged cells may be preferentially committed to death when Parp1 is inactivated.
Louro
Henriqueta
H
Departamento de Genética, Instituto Nacional de Saúde Dr. Ricardo Jorge (INSA), 1649-016 Lisboa, Portugal. henriqueta.louro@insa.min-saude.pt
Faustino
Inês
I
Dias
Anabela
A
Boavida
Maria G
MG
Silva
Maria J
MJ
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D005038:Ethylnitrosourea / Q000633:toxicity*; D007763:Lac Operon; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D015162:Micronucleus Tests; D009154:Mutation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics*; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D013737:Testis / Q000187:drug effects* / Q000378:metabolism
D000477:Alkylating Agents; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D005038:Ethylnitrosourea