Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phase
Checkpoints maintain the order of cell cycle events during DNA damage or incomplete replication. How the checkpoint response is tailored to different phases of the cell cycle remains poorly understood. The S-phase checkpoint for example results in the slowing of replication, which in budding yeast o...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-01-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/63589 |
| _version_ | 1811236158284234752 |
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| author | Mark C Johnson Geylani Can Miguel Monteiro Santos Diana Alexander Philip Zegerman |
| author_facet | Mark C Johnson Geylani Can Miguel Monteiro Santos Diana Alexander Philip Zegerman |
| author_sort | Mark C Johnson |
| collection | DOAJ |
| description | Checkpoints maintain the order of cell cycle events during DNA damage or incomplete replication. How the checkpoint response is tailored to different phases of the cell cycle remains poorly understood. The S-phase checkpoint for example results in the slowing of replication, which in budding yeast occurs by Rad53-dependent inhibition of the initiation factors Sld3 and Dbf4. Despite this, we show here that Rad53 phosphorylates both of these substrates throughout the cell cycle at the same sites as in S-phase, suggesting roles for this pathway beyond S-phase. Indeed, we show that Rad53-dependent inhibition of Sld3 and Dbf4 limits re-replication in G2/M, preventing gene amplification. In addition, we show that inhibition of Sld3 and Dbf4 in G1 prevents premature initiation at all origins at the G1/S transition. This study redefines the scope of the ‘S-phase checkpoint’ with implications for understanding checkpoint function in cancers that lack cell cycle controls. |
| first_indexed | 2024-04-12T12:04:05Z |
| format | Article |
| id | doaj.art-eb7f5eb49ee848a4b14a85c145ea836e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:04:05Z |
| publishDate | 2021-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-eb7f5eb49ee848a4b14a85c145ea836e2022-12-22T03:33:46ZengeLife Sciences Publications LtdeLife2050-084X2021-01-011010.7554/eLife.63589Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phaseMark C Johnson0https://orcid.org/0000-0002-6136-7055Geylani Can1https://orcid.org/0000-0002-1716-7830Miguel Monteiro Santos2https://orcid.org/0000-0002-5594-2682Diana Alexander3https://orcid.org/0000-0002-7785-3170Philip Zegerman4https://orcid.org/0000-0002-5707-1083Wellcome Trust/Cancer Research United Kingdom Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, United KingdomWellcome Trust/Cancer Research United Kingdom Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, United KingdomWellcome Trust/Cancer Research United Kingdom Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, United KingdomWellcome Trust/Cancer Research United Kingdom Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, United KingdomWellcome Trust/Cancer Research United Kingdom Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, United KingdomCheckpoints maintain the order of cell cycle events during DNA damage or incomplete replication. How the checkpoint response is tailored to different phases of the cell cycle remains poorly understood. The S-phase checkpoint for example results in the slowing of replication, which in budding yeast occurs by Rad53-dependent inhibition of the initiation factors Sld3 and Dbf4. Despite this, we show here that Rad53 phosphorylates both of these substrates throughout the cell cycle at the same sites as in S-phase, suggesting roles for this pathway beyond S-phase. Indeed, we show that Rad53-dependent inhibition of Sld3 and Dbf4 limits re-replication in G2/M, preventing gene amplification. In addition, we show that inhibition of Sld3 and Dbf4 in G1 prevents premature initiation at all origins at the G1/S transition. This study redefines the scope of the ‘S-phase checkpoint’ with implications for understanding checkpoint function in cancers that lack cell cycle controls.https://elifesciences.org/articles/63589cell cyclecheckpointsS-phasereplicationRad53genome stability |
| spellingShingle | Mark C Johnson Geylani Can Miguel Monteiro Santos Diana Alexander Philip Zegerman Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phase eLife cell cycle checkpoints S-phase replication Rad53 genome stability |
| title | Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phase |
| title_full | Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phase |
| title_fullStr | Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phase |
| title_full_unstemmed | Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phase |
| title_short | Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phase |
| title_sort | checkpoint inhibition of origin firing prevents inappropriate replication outside of s phase |
| topic | cell cycle checkpoints S-phase replication Rad53 genome stability |
| url | https://elifesciences.org/articles/63589 |
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