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A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression
Accumulating evidence suggests that dormant DNA replication origins play an important role in the recovery of stalled forks. However, their functional interactions with other fork recovery mechanisms have not been tested. We previously reported intrinsic activation of the Fanconi anemia (FA) pathway...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027174/ https://www.ncbi.nlm.nih.gov/pubmed/24589582 http://dx.doi.org/10.1093/nar/gku170 |
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author | Luebben, Spencer W. Kawabata, Tsuyoshi Johnson, Charles S. O'Sullivan, M. Gerard Shima, Naoko |
author_facet | Luebben, Spencer W. Kawabata, Tsuyoshi Johnson, Charles S. O'Sullivan, M. Gerard Shima, Naoko |
author_sort | Luebben, Spencer W. |
collection | PubMed |
description | Accumulating evidence suggests that dormant DNA replication origins play an important role in the recovery of stalled forks. However, their functional interactions with other fork recovery mechanisms have not been tested. We previously reported intrinsic activation of the Fanconi anemia (FA) pathway in a tumor-prone mouse model (Mcm4(chaos3)) with a 60% loss of dormant origins. To understand this further, we introduced a null allele of Fancc (Fancc(−)), encoding a member of the FA core complex, into the Mcm4(chaos3) background. Primary embryonic fibroblasts double homozygous for Mcm4(chaos3) and Fancc(−) (Mcm4(chaos3/chaos3);Fancc(−/−)) showed significantly increased levels of markers of stalled/collapsed forks compared to either single homozygote. Interestingly, a loss of dormant origins also increased the number of sites in which replication was delayed until prophase, regardless of FA pathway activation. These replication defects coincided with substantially elevated levels of genome instability in Mcm4(chaos3/chaos3);Fancc(−/−) cells, resulting in a high rate of perinatal lethality of Mcm4(chaos3/chaos3);Fancc(−/−) mice and the accelerated tumorigenesis of surviving mice. Together, these findings uncover a specialized role of dormant origins in replication completion while also identifying important functional overlaps between dormant origins and the FA pathway in maintaining fork progression, genome stability, normal development and tumor suppression. |
format | Online Article Text |
id | pubmed-4027174 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-40271742014-05-28 A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression Luebben, Spencer W. Kawabata, Tsuyoshi Johnson, Charles S. O'Sullivan, M. Gerard Shima, Naoko Nucleic Acids Res Genome Integrity, Repair and Replication Accumulating evidence suggests that dormant DNA replication origins play an important role in the recovery of stalled forks. However, their functional interactions with other fork recovery mechanisms have not been tested. We previously reported intrinsic activation of the Fanconi anemia (FA) pathway in a tumor-prone mouse model (Mcm4(chaos3)) with a 60% loss of dormant origins. To understand this further, we introduced a null allele of Fancc (Fancc(−)), encoding a member of the FA core complex, into the Mcm4(chaos3) background. Primary embryonic fibroblasts double homozygous for Mcm4(chaos3) and Fancc(−) (Mcm4(chaos3/chaos3);Fancc(−/−)) showed significantly increased levels of markers of stalled/collapsed forks compared to either single homozygote. Interestingly, a loss of dormant origins also increased the number of sites in which replication was delayed until prophase, regardless of FA pathway activation. These replication defects coincided with substantially elevated levels of genome instability in Mcm4(chaos3/chaos3);Fancc(−/−) cells, resulting in a high rate of perinatal lethality of Mcm4(chaos3/chaos3);Fancc(−/−) mice and the accelerated tumorigenesis of surviving mice. Together, these findings uncover a specialized role of dormant origins in replication completion while also identifying important functional overlaps between dormant origins and the FA pathway in maintaining fork progression, genome stability, normal development and tumor suppression. Oxford University Press 2014-05-01 2014-03-03 /pmc/articles/PMC4027174/ /pubmed/24589582 http://dx.doi.org/10.1093/nar/gku170 Text en © 2014 The Author(s). Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) 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 Luebben, Spencer W. Kawabata, Tsuyoshi Johnson, Charles S. O'Sullivan, M. Gerard Shima, Naoko A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression |
title | A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression |
title_full | A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression |
title_fullStr | A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression |
title_full_unstemmed | A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression |
title_short | A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression |
title_sort | concomitant loss of dormant origins and fancc exacerbates genome instability by impairing dna replication fork progression |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027174/ https://www.ncbi.nlm.nih.gov/pubmed/24589582 http://dx.doi.org/10.1093/nar/gku170 |
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