Developmental control of gene copy number by repression of replication initiation and fork progression
Precise DNA replication is crucial for genome maintenance, yet this process has been inherently difficult to study on a genome-wide level in untransformed differentiated metazoan cells. To determine how metazoan DNA replication can be repressed, we examined regions selectively under-replicated in Dr...
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| Format: | Article |
| Language: | en_US |
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Cold Spring Harbor Laboratory Press
2012
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| Online Access: | http://hdl.handle.net/1721.1/74257 https://orcid.org/0000-0002-8305-9125 https://orcid.org/0000-0002-7934-111X |
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| author | Sher, Noa Bell, George W. Li, Sharon Nordman, Jared T. Eng, Thomas Eaton, Matthew Lucas MacAlpine, David M. Orr-Weaver, Terry L. |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Sher, Noa Bell, George W. Li, Sharon Nordman, Jared T. Eng, Thomas Eaton, Matthew Lucas MacAlpine, David M. Orr-Weaver, Terry L. |
| author_sort | Sher, Noa |
| collection | MIT |
| description | Precise DNA replication is crucial for genome maintenance, yet this process has been inherently difficult to study on a genome-wide level in untransformed differentiated metazoan cells. To determine how metazoan DNA replication can be repressed, we examined regions selectively under-replicated in Drosophila polytene salivary glands, and found they are transcriptionally silent and enriched for the repressive H3K27me3 mark. In the first genome-wide analysis of binding of the origin recognition complex (ORC) in a differentiated metazoan tissue, we find that ORC binding is dramatically reduced within these large domains, suggesting reduced initiation as one mechanism leading to under-replication. Inhibition of replication fork progression by the chromatin protein SUUR is an additional repression mechanism to reduce copy number. Although repressive histone marks are removed when SUUR is mutated and copy number restored, neither transcription nor ORC binding is reinstated. Tethering of the SUUR protein to a specific site is insufficient to block replication, however. These results establish that developmental control of DNA replication, at both the initiation and elongation stages, is a mechanism to change gene copy number during differentiation. |
| first_indexed | 2024-09-23T17:02:59Z |
| format | Article |
| id | mit-1721.1/74257 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:02:59Z |
| publishDate | 2012 |
| publisher | Cold Spring Harbor Laboratory Press |
| record_format | dspace |
| spelling | mit-1721.1/742572022-09-29T23:18:24Z Developmental control of gene copy number by repression of replication initiation and fork progression Sher, Noa Bell, George W. Li, Sharon Nordman, Jared T. Eng, Thomas Eaton, Matthew Lucas MacAlpine, David M. Orr-Weaver, Terry L. Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Nordman, Jared T. Eaton, Matthew Lucas Orr-Weaver, Terry L. Precise DNA replication is crucial for genome maintenance, yet this process has been inherently difficult to study on a genome-wide level in untransformed differentiated metazoan cells. To determine how metazoan DNA replication can be repressed, we examined regions selectively under-replicated in Drosophila polytene salivary glands, and found they are transcriptionally silent and enriched for the repressive H3K27me3 mark. In the first genome-wide analysis of binding of the origin recognition complex (ORC) in a differentiated metazoan tissue, we find that ORC binding is dramatically reduced within these large domains, suggesting reduced initiation as one mechanism leading to under-replication. Inhibition of replication fork progression by the chromatin protein SUUR is an additional repression mechanism to reduce copy number. Although repressive histone marks are removed when SUUR is mutated and copy number restored, neither transcription nor ORC binding is reinstated. Tethering of the SUUR protein to a specific site is insufficient to block replication, however. These results establish that developmental control of DNA replication, at both the initiation and elongation stages, is a mechanism to change gene copy number during differentiation. National Institutes of Health (U.S.) (Grant GM57960) American Cancer Society. Research Professor Grant National Institutes of Health (U.S.) (Grant 1U01HG004279) 2012-10-25T18:58:43Z 2012-10-25T18:58:43Z 2011-11 2011-05 Article http://purl.org/eprint/type/JournalArticle 1088-9051 http://hdl.handle.net/1721.1/74257 Sher, N. et al. “Developmental Control of Gene Copy Number by Repression of Replication Initiation and Fork Progression.” Genome Research 22.1 (2011): 64–75. © 2011 by Cold Spring Harbor Laboratory Press https://orcid.org/0000-0002-8305-9125 https://orcid.org/0000-0002-7934-111X en_US http://dx.doi.org/10.1101/gr.126003.111 Genome Research Creative Commons Attribution Non-Commercial http://creativecommons.org/licenses/by-nc/3.0/ application/pdf Cold Spring Harbor Laboratory Press Cold Spring Harbor Laboratory Press |
| spellingShingle | Sher, Noa Bell, George W. Li, Sharon Nordman, Jared T. Eng, Thomas Eaton, Matthew Lucas MacAlpine, David M. Orr-Weaver, Terry L. Developmental control of gene copy number by repression of replication initiation and fork progression |
| title | Developmental control of gene copy number by repression of replication initiation and fork progression |
| title_full | Developmental control of gene copy number by repression of replication initiation and fork progression |
| title_fullStr | Developmental control of gene copy number by repression of replication initiation and fork progression |
| title_full_unstemmed | Developmental control of gene copy number by repression of replication initiation and fork progression |
| title_short | Developmental control of gene copy number by repression of replication initiation and fork progression |
| title_sort | developmental control of gene copy number by repression of replication initiation and fork progression |
| url | http://hdl.handle.net/1721.1/74257 https://orcid.org/0000-0002-8305-9125 https://orcid.org/0000-0002-7934-111X |
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