Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phase
| Autor: | Johnson, Mark C, Can, Geylani, Santos, Miguel Monteiro, Alexander, Diana, Zegerman, Philip |
|---|---|
| Přispěvatelé: | Johnson, Mark C [0000-0002-6136-7055], Can, Geylani [0000-0002-1716-7830], Santos, Miguel Monteiro [0000-0002-5594-2682], Alexander, Diana [0000-0002-7785-3170], Zegerman, Philip [0000-0002-5707-1083], Apollo - University of Cambridge Repository |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Immune checkpoint inhibitors S. cerevisiae Cell Cycle Proteins S Phase chemistry.chemical_compound 0302 clinical medicine Gene duplication Gene expression Biology (General) 0303 health sciences Kinase General Neuroscience General Medicine Cell cycle Chromosomes and Gene Expression Cell biology 030220 oncology & carcinogenesis Phosphorylation Medicine cell cycle checkpoints Research Article chromosomes replication Saccharomyces cerevisiae Proteins DNA damage QH301-705.5 S-phase Science Saccharomyces cerevisiae Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Initiation factor 030304 developmental biology General Immunology and Microbiology biology.organism_classification Replication (computing) Checkpoint Kinase 2 030104 developmental biology chemistry Replication Initiation Rad53 gene expression DNA 030217 neurology & neurosurgery genome stability |
| Zdroj: | eLife, Vol 10 (2021) eLife |
| Popis: | Across eukaryotes, checkpoints maintain the order of cell cycle events in the face of DNA damage or incomplete replication. Although a wide array of DNA lesions activates the checkpoint kinases, whether and how this response differs in different phases of the cell cycle remains poorly understood. The S-phase checkpoint for example results in the slowing of replication, which in the budding yeastSaccharomyces cerevisiaeis caused by Rad53 kinase-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 phase, preventing inappropriate gene amplification events. In addition we show that inhibition of Sld3 and Dbf4 after DNA damage in G1 phase prevents premature replication initiation at all origins at the G1/S transition. This study redefines the scope and specificity of the ‘S-phase checkpoint’ with implications for understanding the roles of this checkpoint in the majority of cancers that lack proper cell cycle controls. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|