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ASAR15, A cis-Acting Locus that Controls Chromosome-Wide Replication Timing and Stability of Human Chromosome 15

DNA replication initiates at multiple sites along each mammalian chromosome at different times during each S phase, following a temporal replication program. We have used a Cre/loxP-based strategy to identify cis-acting elements that control this replication-timing program on individual human chromo...

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Autores principales: Donley, Nathan, Smith, Leslie, Thayer, Mathew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287527/
https://www.ncbi.nlm.nih.gov/pubmed/25569254
http://dx.doi.org/10.1371/journal.pgen.1004923
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author Donley, Nathan
Smith, Leslie
Thayer, Mathew J.
author_facet Donley, Nathan
Smith, Leslie
Thayer, Mathew J.
author_sort Donley, Nathan
collection PubMed
description DNA replication initiates at multiple sites along each mammalian chromosome at different times during each S phase, following a temporal replication program. We have used a Cre/loxP-based strategy to identify cis-acting elements that control this replication-timing program on individual human chromosomes. In this report, we show that rearrangements at a complex locus at chromosome 15q24.3 result in delayed replication and structural instability of human chromosome 15. Characterization of this locus identified long, RNA transcripts that are retained in the nucleus and form a “cloud” on one homolog of chromosome 15. We also found that this locus displays asynchronous replication that is coordinated with other random monoallelic genes on chromosome 15. We have named this locus ASynchronous replication and Autosomal RNA on chromosome 15, or ASAR15. Previously, we found that disruption of the ASAR6 lincRNA gene results in delayed replication, delayed mitotic condensation and structural instability of human chromosome 6. Previous studies in the mouse found that deletion of the Xist gene, from the X chromosome in adult somatic cells, results in a delayed replication and instability phenotype that is indistinguishable from the phenotype caused by disruption of either ASAR6 or ASAR15. In addition, delayed replication and chromosome instability were detected following structural rearrangement of many different human or mouse chromosomes. These observations suggest that all mammalian chromosomes contain similar cis-acting loci. Thus, under this scenario, all mammalian chromosomes contain four distinct types of essential cis-acting elements: origins, telomeres, centromeres and “inactivation/stability centers”, all functioning to promote proper replication, segregation and structural stability of each chromosome.
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spelling pubmed-42875272015-01-12 ASAR15, A cis-Acting Locus that Controls Chromosome-Wide Replication Timing and Stability of Human Chromosome 15 Donley, Nathan Smith, Leslie Thayer, Mathew J. PLoS Genet Research Article DNA replication initiates at multiple sites along each mammalian chromosome at different times during each S phase, following a temporal replication program. We have used a Cre/loxP-based strategy to identify cis-acting elements that control this replication-timing program on individual human chromosomes. In this report, we show that rearrangements at a complex locus at chromosome 15q24.3 result in delayed replication and structural instability of human chromosome 15. Characterization of this locus identified long, RNA transcripts that are retained in the nucleus and form a “cloud” on one homolog of chromosome 15. We also found that this locus displays asynchronous replication that is coordinated with other random monoallelic genes on chromosome 15. We have named this locus ASynchronous replication and Autosomal RNA on chromosome 15, or ASAR15. Previously, we found that disruption of the ASAR6 lincRNA gene results in delayed replication, delayed mitotic condensation and structural instability of human chromosome 6. Previous studies in the mouse found that deletion of the Xist gene, from the X chromosome in adult somatic cells, results in a delayed replication and instability phenotype that is indistinguishable from the phenotype caused by disruption of either ASAR6 or ASAR15. In addition, delayed replication and chromosome instability were detected following structural rearrangement of many different human or mouse chromosomes. These observations suggest that all mammalian chromosomes contain similar cis-acting loci. Thus, under this scenario, all mammalian chromosomes contain four distinct types of essential cis-acting elements: origins, telomeres, centromeres and “inactivation/stability centers”, all functioning to promote proper replication, segregation and structural stability of each chromosome. Public Library of Science 2015-01-08 /pmc/articles/PMC4287527/ /pubmed/25569254 http://dx.doi.org/10.1371/journal.pgen.1004923 Text en © 2015 Donley 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Donley, Nathan
Smith, Leslie
Thayer, Mathew J.
ASAR15, A cis-Acting Locus that Controls Chromosome-Wide Replication Timing and Stability of Human Chromosome 15
title ASAR15, A cis-Acting Locus that Controls Chromosome-Wide Replication Timing and Stability of Human Chromosome 15
title_full ASAR15, A cis-Acting Locus that Controls Chromosome-Wide Replication Timing and Stability of Human Chromosome 15
title_fullStr ASAR15, A cis-Acting Locus that Controls Chromosome-Wide Replication Timing and Stability of Human Chromosome 15
title_full_unstemmed ASAR15, A cis-Acting Locus that Controls Chromosome-Wide Replication Timing and Stability of Human Chromosome 15
title_short ASAR15, A cis-Acting Locus that Controls Chromosome-Wide Replication Timing and Stability of Human Chromosome 15
title_sort asar15, a cis-acting locus that controls chromosome-wide replication timing and stability of human chromosome 15
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287527/
https://www.ncbi.nlm.nih.gov/pubmed/25569254
http://dx.doi.org/10.1371/journal.pgen.1004923
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