Cargando…
Ribosomal DNA copy number loss and sequence variation in cancer
Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number. Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with map...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480814/ https://www.ncbi.nlm.nih.gov/pubmed/28640831 http://dx.doi.org/10.1371/journal.pgen.1006771 |
_version_ | 1783245307249688576 |
---|---|
author | Xu, Baoshan Li, Hua Perry, John M. Singh, Vijay Pratap Unruh, Jay Yu, Zulin Zakari, Musinu McDowell, William Li, Linheng Gerton, Jennifer L. |
author_facet | Xu, Baoshan Li, Hua Perry, John M. Singh, Vijay Pratap Unruh, Jay Yu, Zulin Zakari, Musinu McDowell, William Li, Linheng Gerton, Jennifer L. |
author_sort | Xu, Baoshan |
collection | PubMed |
description | Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number. Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with mapping and analysis. We applied computational and droplet digital PCR approaches to measure rDNA copy number in normal and cancer states in human and mouse genomes. We find that copy number and sequence can change in cancer genomes. Counterintuitively, human cancer genomes show a loss of copies, accompanied by global copy number co-variation. The sequence can also be more variable in the cancer genome. Cancer genomes with lower copies have mutational evidence of mTOR hyperactivity. The PTEN phosphatase is a tumor suppressor that is critical for genome stability and a negative regulator of the mTOR kinase pathway. Surprisingly, but consistent with the human cancer genomes, hematopoietic cancer stem cells from a Pten(-/-) mouse model for leukemia have lower rDNA copy number than normal tissue, despite increased proliferation, rRNA production, and protein synthesis. Loss of copies occurs early and is associated with hypersensitivity to DNA damage. Therefore, copy loss is a recurrent feature in cancers associated with mTOR activation. Ribosomal DNA copy number may be a simple and useful indicator of whether a cancer will be sensitive to DNA damaging treatments. |
format | Online Article Text |
id | pubmed-5480814 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54808142017-07-05 Ribosomal DNA copy number loss and sequence variation in cancer Xu, Baoshan Li, Hua Perry, John M. Singh, Vijay Pratap Unruh, Jay Yu, Zulin Zakari, Musinu McDowell, William Li, Linheng Gerton, Jennifer L. PLoS Genet Research Article Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number. Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with mapping and analysis. We applied computational and droplet digital PCR approaches to measure rDNA copy number in normal and cancer states in human and mouse genomes. We find that copy number and sequence can change in cancer genomes. Counterintuitively, human cancer genomes show a loss of copies, accompanied by global copy number co-variation. The sequence can also be more variable in the cancer genome. Cancer genomes with lower copies have mutational evidence of mTOR hyperactivity. The PTEN phosphatase is a tumor suppressor that is critical for genome stability and a negative regulator of the mTOR kinase pathway. Surprisingly, but consistent with the human cancer genomes, hematopoietic cancer stem cells from a Pten(-/-) mouse model for leukemia have lower rDNA copy number than normal tissue, despite increased proliferation, rRNA production, and protein synthesis. Loss of copies occurs early and is associated with hypersensitivity to DNA damage. Therefore, copy loss is a recurrent feature in cancers associated with mTOR activation. Ribosomal DNA copy number may be a simple and useful indicator of whether a cancer will be sensitive to DNA damaging treatments. Public Library of Science 2017-06-22 /pmc/articles/PMC5480814/ /pubmed/28640831 http://dx.doi.org/10.1371/journal.pgen.1006771 Text en © 2017 Xu 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 Xu, Baoshan Li, Hua Perry, John M. Singh, Vijay Pratap Unruh, Jay Yu, Zulin Zakari, Musinu McDowell, William Li, Linheng Gerton, Jennifer L. Ribosomal DNA copy number loss and sequence variation in cancer |
title | Ribosomal DNA copy number loss and sequence variation in cancer |
title_full | Ribosomal DNA copy number loss and sequence variation in cancer |
title_fullStr | Ribosomal DNA copy number loss and sequence variation in cancer |
title_full_unstemmed | Ribosomal DNA copy number loss and sequence variation in cancer |
title_short | Ribosomal DNA copy number loss and sequence variation in cancer |
title_sort | ribosomal dna copy number loss and sequence variation in cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480814/ https://www.ncbi.nlm.nih.gov/pubmed/28640831 http://dx.doi.org/10.1371/journal.pgen.1006771 |
work_keys_str_mv | AT xubaoshan ribosomaldnacopynumberlossandsequencevariationincancer AT lihua ribosomaldnacopynumberlossandsequencevariationincancer AT perryjohnm ribosomaldnacopynumberlossandsequencevariationincancer AT singhvijaypratap ribosomaldnacopynumberlossandsequencevariationincancer AT unruhjay ribosomaldnacopynumberlossandsequencevariationincancer AT yuzulin ribosomaldnacopynumberlossandsequencevariationincancer AT zakarimusinu ribosomaldnacopynumberlossandsequencevariationincancer AT mcdowellwilliam ribosomaldnacopynumberlossandsequencevariationincancer AT lilinheng ribosomaldnacopynumberlossandsequencevariationincancer AT gertonjenniferl ribosomaldnacopynumberlossandsequencevariationincancer |