Colocalization of sensors is sufficient to activate the DNA damage checkpoint in the absence of damage
Open accessAbstract
Previous work on the DNA damage checkpoint in Saccharomyces cerevisiae has shown that two complexes independently sense DNA lesions: the kinase Mec1-Ddc2 and the PCNA-like 9-1-1 complex. To test whether colocalization of these components is sufficient for checkpoint activation, we fused these checkpoint proteins to the LacI repressor and artificially colocalized these fusions by expressing them in cells harboring Lac operator arrays. We observed Rad53 and Rad9 phosphorylation, Sml1 degradation, and metaphase delay, demonstrating that colocalization of these sensors is sufficient to activate the checkpoint in the absence of DNA damage. Our tethering system allowed us to establish that CDK functions in the checkpoint pathway downstream of damage processing and checkpoint protein recruitment. This CDK dependence is likely, at least in part, through Rad9, since mutation of CDK consensus sites compromised its checkpoint function.
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Co-localization of these complexes is sufficient to trigger at least partial checkpoint signaling even without actual DNA damage.
“The co-localization of these complexes is sufficient to trigger at least a partial checkpoint signaling even in the absence of actual DNA damage [18].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [18]
A DNA lesion is not required for the DNA damage response machinery.
“This conclusion is in line with earlier tethering experiments demonstrating that a DNA lesion is not an obligatory part of the DDR machinery and DDR signaling can occur in its absence, allowing for the possibility of DDR initiation by stimuli other than DNA damage, such as chromatin structure (Bonilla et al., 2008; Soutoglou and Misteli, 2008).”
From Activation of DNA Damage Response Signaling by Condensed Chromatin (2014) · cites this paper as Bonilla et al., 2008
DNA damage response signaling can happen without a DNA lesion.
“This conclusion is in line with earlier tethering experiments demonstrating that a DNA lesion is not an obligatory part of the DDR machinery and DDR signaling can occur in its absence, allowing for the possibility of DDR initiation by stimuli other than DNA damage, such as chromatin structure (Bonilla et al., 2008; Soutoglou and Misteli, 2008).”
From Activation of DNA Damage Response Signaling by Condensed Chromatin (2014) · cites this paper as Bonilla et al., 2008
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“The co-localization of hese complexes is sufficient to trigger at least a partial checkoint signaling even in the absence of actual DNA damage [18].”
Background
- Authors
- Bonilla, C. Y., Melo, J. A., & Toczyski, D. P.
- Affiliations
- University of California, San Francisco (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Toczyski, David Paul
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 30
- Issue
- 3
- Pages
- 267-276
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2879338
- OpenAlex
- W2030829729
- Cited by
- 161
- References
- 58
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 7 · 2022: 1 · 2021: 9 · 2020: 3 · 2019: 7 · 2018: 7 · 2017: 7 · 2016: 4 · 2015: 5 · 2014: 13 · 2013: 10 · 2012: 9
- FWCI
- 10.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (59691)
- National Institute of General Medical Sciences (1R25GM56847, R25GM056847, R01GM059691)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- DNA damage checkpoint, 9-1-1 complex, Rad53 phosphorylation, cyclin-dependent kinases, Saccharomyces cerevisiae
- MeSH terms
- Animals, Chromatin, DNA Damage, Enzyme Activation, Histones, Phosphoproteins, Recombinant Fusion Proteins, Repressor Proteins, Saccharomyces cerevisiae, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Genes, cdc, Cyclin-Dependent Kinases, Protein Subunits, Saccharomyces cerevisiae Proteins, Macromolecular Substances, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Checkpoint Kinase 2
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