Dynamic changes in ORC localization and replication fork progression during tissue differentiation
Background Genomic regions repressed for DNA replication, resulting in either delayed replication in S phase or underreplication in polyploid cells, are thought to be controlled by inhibition of replication origin activation. Studies in Drosophila polytene cells, however, raised the...
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| Format: | Article |
| Language: | English |
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BioMed Central
2018
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| Online Access: | http://hdl.handle.net/1721.1/117577 https://orcid.org/0000-0002-7580-3399 https://orcid.org/0000-0002-7934-111X |
| _version_ | 1826198914018050048 |
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| author | Kashevsky, Helena Von Stetina, Jessica R. Bell, George W. Hua, Brian Orr-Weaver, Terry |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Kashevsky, Helena Von Stetina, Jessica R. Bell, George W. Hua, Brian Orr-Weaver, Terry |
| author_sort | Kashevsky, Helena |
| collection | MIT |
| description | Background
Genomic regions repressed for DNA replication, resulting in either delayed replication in S phase or underreplication in polyploid cells, are thought to be controlled by inhibition of replication origin activation. Studies in Drosophila polytene cells, however, raised the possibility that impeding replication fork progression also plays a major role.
Results
We exploited genomic regions underreplicated (URs) with tissue specificity in Drosophila polytene cells to analyze mechanisms of replication repression. By localizing the Origin Recognition Complex (ORC) in the genome of the larval fat body and comparing this to ORC binding in the salivary gland, we found that sites of ORC binding show extensive tissue specificity. In contrast, there are common domains nearly devoid of ORC in the salivary gland and fat body that also have reduced density of ORC binding sites in diploid cells. Strikingly, domains lacking ORC can still be replicated in some polytene tissues, showing absence of ORC and origins is insufficient to repress replication. Analysis of the width and location of the URs with respect to ORC position indicates that whether or not a genomic region lacking ORC is replicated is controlled by whether replication forks formed outside the region are inhibited.
Conclusions
These studies demonstrate that inhibition of replication fork progression can block replication across genomic regions that constitutively lack ORC. Replication fork progression can be inhibited in both tissue-specific and genome region-specific ways. Consequently, when evaluating sources of genome instability it is important to consider altered control of replication forks in response to differentiation. |
| first_indexed | 2024-09-23T11:11:55Z |
| format | Article |
| id | mit-1721.1/117577 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:11:55Z |
| publishDate | 2018 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | mit-1721.1/1175772022-10-01T01:58:13Z Dynamic changes in ORC localization and replication fork progression during tissue differentiation Kashevsky, Helena Von Stetina, Jessica R. Bell, George W. Hua, Brian Orr-Weaver, Terry Massachusetts Institute of Technology. Department of Biology Hua, Brian Orr-Weaver, Terry Background Genomic regions repressed for DNA replication, resulting in either delayed replication in S phase or underreplication in polyploid cells, are thought to be controlled by inhibition of replication origin activation. Studies in Drosophila polytene cells, however, raised the possibility that impeding replication fork progression also plays a major role. Results We exploited genomic regions underreplicated (URs) with tissue specificity in Drosophila polytene cells to analyze mechanisms of replication repression. By localizing the Origin Recognition Complex (ORC) in the genome of the larval fat body and comparing this to ORC binding in the salivary gland, we found that sites of ORC binding show extensive tissue specificity. In contrast, there are common domains nearly devoid of ORC in the salivary gland and fat body that also have reduced density of ORC binding sites in diploid cells. Strikingly, domains lacking ORC can still be replicated in some polytene tissues, showing absence of ORC and origins is insufficient to repress replication. Analysis of the width and location of the URs with respect to ORC position indicates that whether or not a genomic region lacking ORC is replicated is controlled by whether replication forks formed outside the region are inhibited. Conclusions These studies demonstrate that inhibition of replication fork progression can block replication across genomic regions that constitutively lack ORC. Replication fork progression can be inhibited in both tissue-specific and genome region-specific ways. Consequently, when evaluating sources of genome instability it is important to consider altered control of replication forks in response to differentiation. National Institutes of Health (U.S.) (Grant HG004279) National Institutes of Health (U.S.) (Grant GM57940) National Institutes of Health (U.S.) (Grant GM118098) 2018-08-28T14:52:00Z 2018-08-28T14:52:00Z 2018-08 2018-05 2018-08-26T03:21:27Z Article http://purl.org/eprint/type/JournalArticle 1471-2164 http://hdl.handle.net/1721.1/117577 Hua, Brian L. et al. "Dynamic changes in ORC localization and replication fork progression during tissue differentiation." BMC Genomics 2018, 19 (August 2018): 623 © 2018 The Author(s) https://orcid.org/0000-0002-7580-3399 https://orcid.org/0000-0002-7934-111X en https://doi.org/10.1186/s12864-018-4992-3 BMC Genomics Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ The Author(s). application/pdf BioMed Central BioMed Central |
| spellingShingle | Kashevsky, Helena Von Stetina, Jessica R. Bell, George W. Hua, Brian Orr-Weaver, Terry Dynamic changes in ORC localization and replication fork progression during tissue differentiation |
| title | Dynamic changes in ORC localization and replication fork progression during tissue differentiation |
| title_full | Dynamic changes in ORC localization and replication fork progression during tissue differentiation |
| title_fullStr | Dynamic changes in ORC localization and replication fork progression during tissue differentiation |
| title_full_unstemmed | Dynamic changes in ORC localization and replication fork progression during tissue differentiation |
| title_short | Dynamic changes in ORC localization and replication fork progression during tissue differentiation |
| title_sort | dynamic changes in orc localization and replication fork progression during tissue differentiation |
| url | http://hdl.handle.net/1721.1/117577 https://orcid.org/0000-0002-7580-3399 https://orcid.org/0000-0002-7934-111X |
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