Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 82-88 |
| Number of pages | 7 |
| Journal | Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis |
| Volume | 640 |
| Issue number | 1-2 |
| DOIs | |
| Publication status | Published - 2 Apr 2008 |
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Keywords
- Deletions
- LacZ mice
- MNU
- Mutation pattern
- Parp1
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Mutagenic effects of poly (ADP-ribose) polymerase-1 deficiency in transgenic mice. / Louro, Henriqueta; Pinheiro, Inês; Costa, Paula; Sousa, Carla; Dias, Anabela; Boavida, Maria G.; Silva, Maria J.
In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 640, No. 1-2, 02.04.2008, p. 82-88.Research output: Contribution to journal › Article
TY - JOUR
T1 - Mutagenic effects of poly (ADP-ribose) polymerase-1 deficiency in transgenic mice
AU - Louro, Henriqueta
AU - Pinheiro, Inês
AU - Costa, Paula
AU - Sousa, Carla
AU - Dias, Anabela
AU - Boavida, Maria G.
AU - Silva, Maria J.
PY - 2008/4/2
Y1 - 2008/4/2
N2 - 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.
AB - 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.
KW - Deletions
KW - LacZ mice
KW - MNU
KW - Mutation pattern
KW - Parp1
UR - http://www.scopus.com/inward/record.url?scp=40649113074&partnerID=8YFLogxK
U2 - 10.1016/j.mrfmmm.2007.12.003
DO - 10.1016/j.mrfmmm.2007.12.003
M3 - Article
VL - 640
SP - 82
EP - 88
JO - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
JF - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
SN - 0027-5107
IS - 1-2
ER -