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Effect of minichromosome maintenance protein 2 deficiency on the locations of DNA replication origins

Minichromosome maintenance (MCM) proteins are loaded onto chromatin during G1-phase and define potential locations of DNA replication initiation. MCM protein deficiency results in genome instability and high rates of cancer in mouse models. Here we develop a method of nascent strand capture and rele...

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Autores principales: Kunnev, Dimiter, Freeland, Amy, Qin, Maochun, Leach, Robert W., Wang, Jianmin, Shenoy, Rajani M., Pruitt, Steven C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381527/
https://www.ncbi.nlm.nih.gov/pubmed/25762552
http://dx.doi.org/10.1101/gr.176099.114
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author Kunnev, Dimiter
Freeland, Amy
Qin, Maochun
Leach, Robert W.
Wang, Jianmin
Shenoy, Rajani M.
Pruitt, Steven C.
author_facet Kunnev, Dimiter
Freeland, Amy
Qin, Maochun
Leach, Robert W.
Wang, Jianmin
Shenoy, Rajani M.
Pruitt, Steven C.
author_sort Kunnev, Dimiter
collection PubMed
description Minichromosome maintenance (MCM) proteins are loaded onto chromatin during G1-phase and define potential locations of DNA replication initiation. MCM protein deficiency results in genome instability and high rates of cancer in mouse models. Here we develop a method of nascent strand capture and release and show that MCM2 deficiency reduces DNA replication initiation in gene-rich regions of the genome. DNA structural properties are shown to correlate with sequence motifs associated with replication origins and with locations that are preferentially affected by MCM2 deficiency. Reduced nascent strand density correlates with sites of recurrent focal CNVs in tumors arising in MCM2-deficient mice, consistent with a direct relationship between sites of reduced DNA replication initiation and genetic damage. Between 10% and 90% of human tumors, depending on type, carry heterozygous loss or mutation of one or more MCM2-7 genes, which is expected to compromise DNA replication origin licensing and result in elevated rates of genome damage at a subset of gene-rich locations.
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spelling pubmed-43815272015-10-01 Effect of minichromosome maintenance protein 2 deficiency on the locations of DNA replication origins Kunnev, Dimiter Freeland, Amy Qin, Maochun Leach, Robert W. Wang, Jianmin Shenoy, Rajani M. Pruitt, Steven C. Genome Res Method Minichromosome maintenance (MCM) proteins are loaded onto chromatin during G1-phase and define potential locations of DNA replication initiation. MCM protein deficiency results in genome instability and high rates of cancer in mouse models. Here we develop a method of nascent strand capture and release and show that MCM2 deficiency reduces DNA replication initiation in gene-rich regions of the genome. DNA structural properties are shown to correlate with sequence motifs associated with replication origins and with locations that are preferentially affected by MCM2 deficiency. Reduced nascent strand density correlates with sites of recurrent focal CNVs in tumors arising in MCM2-deficient mice, consistent with a direct relationship between sites of reduced DNA replication initiation and genetic damage. Between 10% and 90% of human tumors, depending on type, carry heterozygous loss or mutation of one or more MCM2-7 genes, which is expected to compromise DNA replication origin licensing and result in elevated rates of genome damage at a subset of gene-rich locations. Cold Spring Harbor Laboratory Press 2015-04 /pmc/articles/PMC4381527/ /pubmed/25762552 http://dx.doi.org/10.1101/gr.176099.114 Text en © 2015 Kunnev et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Method
Kunnev, Dimiter
Freeland, Amy
Qin, Maochun
Leach, Robert W.
Wang, Jianmin
Shenoy, Rajani M.
Pruitt, Steven C.
Effect of minichromosome maintenance protein 2 deficiency on the locations of DNA replication origins
title Effect of minichromosome maintenance protein 2 deficiency on the locations of DNA replication origins
title_full Effect of minichromosome maintenance protein 2 deficiency on the locations of DNA replication origins
title_fullStr Effect of minichromosome maintenance protein 2 deficiency on the locations of DNA replication origins
title_full_unstemmed Effect of minichromosome maintenance protein 2 deficiency on the locations of DNA replication origins
title_short Effect of minichromosome maintenance protein 2 deficiency on the locations of DNA replication origins
title_sort effect of minichromosome maintenance protein 2 deficiency on the locations of dna replication origins
topic Method
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381527/
https://www.ncbi.nlm.nih.gov/pubmed/25762552
http://dx.doi.org/10.1101/gr.176099.114
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