Caffeine impairs resection during DNA break repair by reducing the levels of nucleases Sae2 and Dna2
Tsabar M, Eapen VV, Eapen VV, Mason JM, Memisoglu G, Waterman DP, Long MJ, Bishop DK, Haber JE
Nucleic acids research · 47 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- In vitro/mechanistic study (classified by our AI screen)
- Studied in
- Cells or lab samples
- Main outcome
- Mechanisms only
Who paid for it
- Funding
- Independent funding
- Nonprofit
- Howard Hughes Medical Institute
- University or hospital
- Brandeis University
- Government
- National Institutes of Health
- Government
- National Cancer Institute
- Government
- National Institute of General Medical Sciences
- Government
- NIGMS NIH HHS
- Government
- NCI NIH HHS
- Grants
- National Institute of General Medical Sciences (GM61766); National Cancer Institute (5T32CA009594); National Institute of General Medical Sciences (R01 GM020056); National Institute of General Medical Sciences (GM-20056); National Institute of General Medical Sciences (R37 GM020056); National Institute of General Medical Sciences (R01-GM061766); National Institute of General Medical Sciences (GM50936); National Institute of General Medical Sciences (T32-GM-007122)
Based on 7 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2015-05-27 · Nucleic Acids Res · vol. 43 · issue 14 · pp. 6889–6901
- Publisher
- Oxford University Press
- Cited
- 65 citations · more than 92% of similar papers · 3.0× the field average
- Impact
- Top 10% most cited in its field
- References
- 97 works
- Access
- Open access (journal) · CC-BY
- Research areas
- DNA Repair Mechanisms · Microtubule and mitosis dynamics · Cancer-related Molecular Pathways
- Keywords
- Biology, DNA damage, G2-M DNA damage checkpoint, RAD51, Homologous recombination, Genome instability, Cell biology, DNA repair, Histone, Kinase, Cycloheximide, Phosphorylation, Nuclease, DNA, Molecular biology, Biochemistry, Cell cycle, Cell cycle checkpoint, Cell, Protein biosynthesis
- MeSH
- hela cells, humans, saccharomyces cerevisiae, caffeine, proteasome endopeptidase complex, endonucleases, dna helicases, intracellular signaling peptides and proteins, saccharomyces cerevisiae proteins, histones, dna repair, rad51 recombinase, replication protein a, dna breaks, double-stranded, protein serine-threonine kinases
8 authors
From US
- Michael TsabarBrandeis University
- Vinay V. EapenBrandeis University
- Jennifer M. MasonUniversity of Chicago
- Gönen MemişoğluBrandeis University
- David P. WatermanBrandeis University
- Marcus J. C. LongBrandeis University
Abstract
In response to chromosomal double-strand breaks (DSBs), eukaryotic cells activate the DNA damage checkpoint, which is orchestrated by the PI3 kinase-like protein kinases ATR and ATM (Mec1 and Tel1 in budding yeast). Following DSB formation, Mec1 and Tel1 phosphorylate histone H2A on serine 129 (known as γ-H2AX). We used caffeine to inhibit the checkpoint kinases after DSB induction. We show that prolonged phosphorylation of H2A-S129 does not require continuous Mec1 and Tel1 activity. Unexpectedly, caffeine treatment impaired homologous recombination by inhibiting 5' to 3' end resection, independent of Mec1 and Tel1 inhibition. Caffeine treatment led to the rapid loss, by proteasomal degradation, of both Sae2, a nuclease that plays a role in early steps of resection, and Dna2, a nuclease that facilitates one of two extensive resection pathways. Sae2's instability is evident in the absence of DNA damage. A similar loss is seen when protein synthesis is inhibited by cycloheximide. Caffeine treatment had similar effects on irradiated HeLa cells, blocking the formation of RPA and Rad51 foci that depend on 5' to 3' resection of broken chromosome ends. Our findings provide insight toward the use of caffeine as a DNA damage-sensitizing agent in cancer cells.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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