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PARP1 suppresses homologous recombination events in mice in vivo
Recent studies suggest that PARP1 inhibitors, several of which are currently in clinical trial, may selectively kill BRCA1/2 mutant cancers cells. It is thought that the success of this therapy is based on immitigable lethal DNA damage in the cancer cells resultant from the concurrent loss or inhibi...
Autores principales: | , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995050/ https://www.ncbi.nlm.nih.gov/pubmed/20660013 http://dx.doi.org/10.1093/nar/gkq624 |
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author | Claybon, Alison Karia, Bijal Bruce, Crystal Bishop, Alexander J. R. |
author_facet | Claybon, Alison Karia, Bijal Bruce, Crystal Bishop, Alexander J. R. |
author_sort | Claybon, Alison |
collection | PubMed |
description | Recent studies suggest that PARP1 inhibitors, several of which are currently in clinical trial, may selectively kill BRCA1/2 mutant cancers cells. It is thought that the success of this therapy is based on immitigable lethal DNA damage in the cancer cells resultant from the concurrent loss or inhibition of two DNA damage repair pathways: single-strand break (SSB) repair and homologous recombination repair (HRR). Presumably, inhibition of PARP1 activity obstructs the repair of SSBs and during DNA replication, these lesions cause replication fork collapse and are transformed into substrates for HRR. In fact, several previous studies have indicated a hyper-recombinogenic phenotype in the absence of active PARP1 in vitro or in response to DNA damaging agents. In this study, we demonstrate an increased frequency of spontaneous HRR in vivo in the absence of PARP1 using the p(un) assay. Furthermore, we found that the HRR events that occur in Parp1 nullizygous mice are associated with a significant increase in large, clonal events, as opposed to the usually more frequent single cell events, suggesting an effect in replicating cells. In conclusion, our data demonstrates that PARP1 inhibits spontaneous HRR events, and supports the model of DNA replication transformation of SSBs into HRR substrates. |
format | Text |
id | pubmed-2995050 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-29950502010-12-01 PARP1 suppresses homologous recombination events in mice in vivo Claybon, Alison Karia, Bijal Bruce, Crystal Bishop, Alexander J. R. Nucleic Acids Res Genome Integrity, Repair and Replication Recent studies suggest that PARP1 inhibitors, several of which are currently in clinical trial, may selectively kill BRCA1/2 mutant cancers cells. It is thought that the success of this therapy is based on immitigable lethal DNA damage in the cancer cells resultant from the concurrent loss or inhibition of two DNA damage repair pathways: single-strand break (SSB) repair and homologous recombination repair (HRR). Presumably, inhibition of PARP1 activity obstructs the repair of SSBs and during DNA replication, these lesions cause replication fork collapse and are transformed into substrates for HRR. In fact, several previous studies have indicated a hyper-recombinogenic phenotype in the absence of active PARP1 in vitro or in response to DNA damaging agents. In this study, we demonstrate an increased frequency of spontaneous HRR in vivo in the absence of PARP1 using the p(un) assay. Furthermore, we found that the HRR events that occur in Parp1 nullizygous mice are associated with a significant increase in large, clonal events, as opposed to the usually more frequent single cell events, suggesting an effect in replicating cells. In conclusion, our data demonstrates that PARP1 inhibits spontaneous HRR events, and supports the model of DNA replication transformation of SSBs into HRR substrates. Oxford University Press 2010-11 2010-07-21 /pmc/articles/PMC2995050/ /pubmed/20660013 http://dx.doi.org/10.1093/nar/gkq624 Text en © The Author(s) 2010. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/2.5 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Genome Integrity, Repair and Replication Claybon, Alison Karia, Bijal Bruce, Crystal Bishop, Alexander J. R. PARP1 suppresses homologous recombination events in mice in vivo |
title | PARP1 suppresses homologous recombination events in mice in vivo |
title_full | PARP1 suppresses homologous recombination events in mice in vivo |
title_fullStr | PARP1 suppresses homologous recombination events in mice in vivo |
title_full_unstemmed | PARP1 suppresses homologous recombination events in mice in vivo |
title_short | PARP1 suppresses homologous recombination events in mice in vivo |
title_sort | parp1 suppresses homologous recombination events in mice in vivo |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995050/ https://www.ncbi.nlm.nih.gov/pubmed/20660013 http://dx.doi.org/10.1093/nar/gkq624 |
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