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The DNA resection protein CtIP promotes mammary tumorigenesis
Many DNA repair factors act to suppress tumor formation by preserving genomic stability. Similarly, the CtIP protein, which interacts with the BRCA1 tumor suppressor, is also thought to have tumor suppression activity. Through its role in DNA end resection, CtIP facilitates DNA double-strand break (...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078005/ https://www.ncbi.nlm.nih.gov/pubmed/27058754 http://dx.doi.org/10.18632/oncotarget.8605 |
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author | Reczek, Colleen R. Shakya, Reena Miteva, Yana Szabolcs, Matthias Ludwig, Thomas Baer, Richard |
author_facet | Reczek, Colleen R. Shakya, Reena Miteva, Yana Szabolcs, Matthias Ludwig, Thomas Baer, Richard |
author_sort | Reczek, Colleen R. |
collection | PubMed |
description | Many DNA repair factors act to suppress tumor formation by preserving genomic stability. Similarly, the CtIP protein, which interacts with the BRCA1 tumor suppressor, is also thought to have tumor suppression activity. Through its role in DNA end resection, CtIP facilitates DNA double-strand break (DSB) repair by homologous recombination (DSBR-HR) and microhomology-mediated end joining (MMEJ). In addition, however, CtIP has also been implicated in the formation of aberrant chromosomal rearrangements in an MMEJ-dependent manner, an activity that could potentially promote tumor development by increasing genome instability. To clarify whether CtIP acts in vivo to suppress or promote tumorigenesis, we have examined its oncogenic potential in mouse models of human breast cancer. Surprisingly, mice heterozygous for a null Ctip allele did not display an increased susceptibility to tumor formation. Moreover, mammary-specific biallelic CtIP ablation did not elicit breast tumors in a manner reminiscent of BRCA1 loss. Instead, CtIP inactivation dramatically reduced the kinetics of mammary tumorigenesis in mice bearing mammary-specific lesions of the p53 gene. Thus, unlike other repair factors, CtIP is not a tumor suppressor, but has oncogenic properties that can promote tumorigenesis, consistent with its ability to facilitate MMEJ-dependent chromosomal instability. Consequently, inhibition of CtIP-mediated MMEJ may prove effective against tumor types, such as human breast cancer, that display MMEJ-dependent chromosomal rearrangements. |
format | Online Article Text |
id | pubmed-5078005 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-50780052016-10-28 The DNA resection protein CtIP promotes mammary tumorigenesis Reczek, Colleen R. Shakya, Reena Miteva, Yana Szabolcs, Matthias Ludwig, Thomas Baer, Richard Oncotarget Research Paper Many DNA repair factors act to suppress tumor formation by preserving genomic stability. Similarly, the CtIP protein, which interacts with the BRCA1 tumor suppressor, is also thought to have tumor suppression activity. Through its role in DNA end resection, CtIP facilitates DNA double-strand break (DSB) repair by homologous recombination (DSBR-HR) and microhomology-mediated end joining (MMEJ). In addition, however, CtIP has also been implicated in the formation of aberrant chromosomal rearrangements in an MMEJ-dependent manner, an activity that could potentially promote tumor development by increasing genome instability. To clarify whether CtIP acts in vivo to suppress or promote tumorigenesis, we have examined its oncogenic potential in mouse models of human breast cancer. Surprisingly, mice heterozygous for a null Ctip allele did not display an increased susceptibility to tumor formation. Moreover, mammary-specific biallelic CtIP ablation did not elicit breast tumors in a manner reminiscent of BRCA1 loss. Instead, CtIP inactivation dramatically reduced the kinetics of mammary tumorigenesis in mice bearing mammary-specific lesions of the p53 gene. Thus, unlike other repair factors, CtIP is not a tumor suppressor, but has oncogenic properties that can promote tumorigenesis, consistent with its ability to facilitate MMEJ-dependent chromosomal instability. Consequently, inhibition of CtIP-mediated MMEJ may prove effective against tumor types, such as human breast cancer, that display MMEJ-dependent chromosomal rearrangements. Impact Journals LLC 2016-04-06 /pmc/articles/PMC5078005/ /pubmed/27058754 http://dx.doi.org/10.18632/oncotarget.8605 Text en Copyright: © 2016 Reczek et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Reczek, Colleen R. Shakya, Reena Miteva, Yana Szabolcs, Matthias Ludwig, Thomas Baer, Richard The DNA resection protein CtIP promotes mammary tumorigenesis |
title | The DNA resection protein CtIP promotes mammary tumorigenesis |
title_full | The DNA resection protein CtIP promotes mammary tumorigenesis |
title_fullStr | The DNA resection protein CtIP promotes mammary tumorigenesis |
title_full_unstemmed | The DNA resection protein CtIP promotes mammary tumorigenesis |
title_short | The DNA resection protein CtIP promotes mammary tumorigenesis |
title_sort | dna resection protein ctip promotes mammary tumorigenesis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078005/ https://www.ncbi.nlm.nih.gov/pubmed/27058754 http://dx.doi.org/10.18632/oncotarget.8605 |
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