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SIRT1 Deacetylates TopBP1 and Modulates Intra-S-Phase Checkpoint and DNA Replication Origin Firing
- Source :
- International Journal of Biological Sciences
- Publication Year :
- 2014
- Publisher :
- Ivyspring International Publisher, 2014.
-
Abstract
- SIRT1, the mammalian homolog of yeast Sir2, is a founding member of a family of 7 protein and histone deacetylases that are involved in numerous biological functions. Previous studies revealed that SIRT1 deficiency results in genome instability, which eventually leads to cancer formation, yet the underlying mechanism is unclear. To investigate this, we conducted a proteomics study and found that SIRT1 interacted with many proteins involved in replication fork protection and origin firing. We demonstrated that loss of SIRT1 resulted in increased replication origin firing, asymmetric fork progression, defective intra-S-phase checkpoint, and chromosome damage. Mechanistically, SIRT1 deacetylates and affects the activity of TopBP1, which plays an essential role in DNA replication fork protection and replication origin firing. Our study demonstrated that ectopic over-expression of the deacetylated form of TopBP1 in SIRT1 mutant cells repressed replication origin firing, while the acetylated form of TopBP1 lost this function. Thus, SIRT1 acts upstream of TopBP1 and plays an essential role in maintaining genome stability by modulating DNA replication fork initiation and the intra-S-phase cell cycle checkpoint.
- Subjects :
- Blotting, Western
Genetic Vectors
Intra-S-phase checkpoint
Replication Origin
Biology
Genetic stability
Pre-replication complex
Applied Microbiology and Biotechnology
Genomic Instability
Mass Spectrometry
Replication fork protection
Mice
SIRT1
Minichromosome maintenance
Control of chromosome duplication
Sirtuin 1
Animals
Humans
Immunoprecipitation
RNA, Small Interfering
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Genetics
Mice, Knockout
Lentivirus
TopBP1
Acetylation
Cell Biology
DNA Replication Fork
DNA replication origin
DNA replication fork
enzymes and coenzymes (carbohydrates)
Licensing factor
HEK293 Cells
Bromodeoxyuridine
Cytogenetic Analysis
S Phase Cell Cycle Checkpoints
Origin recognition complex
biological phenomena, cell phenomena, and immunity
Carrier Proteins
Developmental Biology
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 14492288
- Volume :
- 10
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- International Journal of Biological Sciences
- Accession number :
- edsair.doi.dedup.....f947268d7f7236d28627e952aeafa4c7