Mutagenic effects of poly (ADP-ribose) polymerase-1 deficiency in transgenic mice.
Poly (ADP-ribose) polymerase-1 (Parp1) plays a central role in the maintenance of genomic integrity and has been unequivocally associated to DNA base excision repair (BER) but its involvement in double-strand break (DSB) repair pathways remains unclear. In this work, using transgenic Parp1-deficient mice harbouring the lacZ reporter gene, we provide in vivo evidence that Parp1 contributes to the prevention of deletions/insertions in testis following an alkylation insult. In response to N-Methyl-N-Nitrosurea (MNU) treatment no significant difference in the mutant frequency (MF) in the liver and testis could be attributed to Parp1 status, given that both Parp1(+/+) and Parp1(-/-) mice showed a similar significant increase in the overall MF. However, restriction analysis of MNU-induced mutants evidenced a shift in the distribution of mutations between deletions/insertions and point mutations in testis, but not in the liver, dependent on the Parp1 status. A significant higher frequency of deletions/insertions was observed in testis from Parp1(-/-) in comparison to Parp1(+/+) mice, whereas point mutations were not significantly affected. Overall, our findings show that Parp1 participates in the prevention of deletions/insertions induced by methylating agents and that organ-specific factors may influence its capacity to protect against genotoxic damage.
Louro
Henriqueta
H
Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge (INSA), Av. Padre Cruz, 1649-016 Lisboa, Portugal. henriqueta.louro@insa.min-saude.pt
Pinheiro
Inês
I
Costa
Paula
P
Sousa
Carla
C
Dias
Anabela
A
Boavida
Maria G
MG
Silva
Maria J
MJ
D000818:Animals; D007763:Lac Operon; D008099:Liver / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D017354:Point Mutation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency*; D017384:Sequence Deletion; D013737:Testis / Q000648:ultrastructure
C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases