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A Signature of Genomic Instability Resulting from Deficient Replication Licensing

Insufficient licensing of DNA replication origins has been shown to result in genome instability, stem cell deficiency, and cancers. However, it is unclear whether the DNA damage resulting from deficient replication licensing occurs generally or if specific sites are preferentially affected. To map...

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Autores principales: Pruitt, Steven C., Qin, Maochun, Wang, Jianmin, Kunnev, Dimiter, Freeland, Amy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242545/
https://www.ncbi.nlm.nih.gov/pubmed/28045896
http://dx.doi.org/10.1371/journal.pgen.1006547
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author Pruitt, Steven C.
Qin, Maochun
Wang, Jianmin
Kunnev, Dimiter
Freeland, Amy
author_facet Pruitt, Steven C.
Qin, Maochun
Wang, Jianmin
Kunnev, Dimiter
Freeland, Amy
author_sort Pruitt, Steven C.
collection PubMed
description Insufficient licensing of DNA replication origins has been shown to result in genome instability, stem cell deficiency, and cancers. However, it is unclear whether the DNA damage resulting from deficient replication licensing occurs generally or if specific sites are preferentially affected. To map locations of ongoing DNA damage in vivo, the DNAs present in red blood cell micronuclei were sequenced. Many micronuclei are the product of DNA breaks that leave acentromeric remnants that failed to segregate during mitosis and should reflect the locations of breaks. To validate the approach we show that micronuclear sequences identify known common fragile sites under conditions that induce breaks at these locations (hydroxyurea). In MCM2 deficient mice a different set of preferred breakage sites is identified that includes the tumor suppressor gene Tcf3, which is known to contribute to T-lymphocytic leukemias that arise in these mice, and the 45S rRNA gene repeats.
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spelling pubmed-52425452017-02-28 A Signature of Genomic Instability Resulting from Deficient Replication Licensing Pruitt, Steven C. Qin, Maochun Wang, Jianmin Kunnev, Dimiter Freeland, Amy PLoS Genet Research Article Insufficient licensing of DNA replication origins has been shown to result in genome instability, stem cell deficiency, and cancers. However, it is unclear whether the DNA damage resulting from deficient replication licensing occurs generally or if specific sites are preferentially affected. To map locations of ongoing DNA damage in vivo, the DNAs present in red blood cell micronuclei were sequenced. Many micronuclei are the product of DNA breaks that leave acentromeric remnants that failed to segregate during mitosis and should reflect the locations of breaks. To validate the approach we show that micronuclear sequences identify known common fragile sites under conditions that induce breaks at these locations (hydroxyurea). In MCM2 deficient mice a different set of preferred breakage sites is identified that includes the tumor suppressor gene Tcf3, which is known to contribute to T-lymphocytic leukemias that arise in these mice, and the 45S rRNA gene repeats. Public Library of Science 2017-01-03 /pmc/articles/PMC5242545/ /pubmed/28045896 http://dx.doi.org/10.1371/journal.pgen.1006547 Text en © 2017 Pruitt et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Pruitt, Steven C.
Qin, Maochun
Wang, Jianmin
Kunnev, Dimiter
Freeland, Amy
A Signature of Genomic Instability Resulting from Deficient Replication Licensing
title A Signature of Genomic Instability Resulting from Deficient Replication Licensing
title_full A Signature of Genomic Instability Resulting from Deficient Replication Licensing
title_fullStr A Signature of Genomic Instability Resulting from Deficient Replication Licensing
title_full_unstemmed A Signature of Genomic Instability Resulting from Deficient Replication Licensing
title_short A Signature of Genomic Instability Resulting from Deficient Replication Licensing
title_sort signature of genomic instability resulting from deficient replication licensing
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242545/
https://www.ncbi.nlm.nih.gov/pubmed/28045896
http://dx.doi.org/10.1371/journal.pgen.1006547
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