Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway
Open accessAbstract
The large protein kinases, ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR), orchestrate DNA damage checkpoint pathways. In budding yeast, ATM and ATR homologs are encoded by TEL1 and MEC1, respectively. The Mre11 complex consists of two highly related proteins, Mre11 and Rad50, and a third protein, Xrs2 in budding yeast or Nbs1 in mammals. The Mre11 complex controls the ATM/Tel1 signaling pathway in response to double-strand break (DSB) induction. We show here that the Mre11 complex functions together with exonuclease 1 (Exo1) in activation of the Mec1 signaling pathway after DNA damage and replication block. Mec1 controls the checkpoint responses following UV irradiation as well as DSB induction. Correspondingly, the Mre11 complex and Exo1 play an overlapping role in activation of DSB- and UV-induced checkpoints. The Mre11 complex and Exo1 collaborate in producing long single-stranded DNA (ssDNA) tails at DSB ends and promote Mec1 association with the DSBs. The Ddc1-Mec3-Rad17 complex associates with sites of DNA damage and modulates the Mec1 signaling pathway. However, Ddc1 association with DSBs does not require the function of the Mre11 complex and Exo1. Mec1 controls checkpoint responses to stalled DNA replication as well. Accordingly, the Mre11 complex and Exo1 contribute to activation of the replication checkpoint pathway. Our results provide a model in which the Mre11 complex and Exo1 cooperate in generating long ssDNA tracts and thereby facilitate Mec1 association with sites of DNA damage or replication block.
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UV irradiation causes accumulation of long ssDNA regions in yeast chromosomes that depend on NER and Exo1 and correlate with Mec1 kinase activation.
“This work shows that UV irradiation causes the accumulation, in yeast chromosomes, of long ssDNA regions that are dependent upon NER and Exo1 and correlate with Mec1 kinase activation.”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [60]
In non-cycling yeast, full and prompt checkpoint activity after UV requires NER and also Exo1 nuclease activity.
“In order to achieve a full and prompt checkpoint activity after UV irradiation in non cycling yeast cells, NER is necessary but not sufficient: in fact, the nuclease activity of Exo1 is also required [60,61].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [60]
Normal NER intermediates are not directly responsible for activating checkpoint kinases.
“Recent work shed light on these problems, showing that normal NER-intermediates are not directly responsible for activating checkpoint kinases.”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [60]
DNA nucleases such as DNA2 and Exo1 contribute to double-strand break end resection and the subsequent ATM-to-ATR transition.
“DNA nucleases (such as DNA2 and Exo1) also contribute to the DSB end resection and subsequent ATM-ATR transition [221]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [221]
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- Authors
- Nakada, D., Hirano, Y., & Sugimoto, K.
- Affiliations
- Rutgers New Jersey Medical School (US)
- Corresponding author
- Sugimoto, Katsunori
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2004-11
- Volume
- 24
- Issue
- 22
- Pages
- 10016-10025
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC525484
- OpenAlex
- W2110555186
- Cited by
- 113
- References
- 68
- Citations by year
- 2023: 2 · 2022: 1 · 2019: 1 · 2018: 2 · 2017: 5 · 2016: 2 · 2015: 5 · 2014: 4 · 2013: 9 · 2012: 4
- FWCI
- 5.09
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- Mre11 complex, EXO1, Mec1, DNA damage checkpoint, DNA double-strand breaks, single-stranded DNA, DNA end resection, S-phase checkpoint, UV-induced DNA damage, Tel1, Saccharomyces cerevisiae
- MeSH terms
- DNA Damage, DNA Replication, DNA-Binding Proteins, DNA, Fungal, Endodeoxyribonucleases, Exodeoxyribonucleases, Fungal Proteins, Genes, Fungal, Models, Biological, Mutation, Phleomycins, Phosphoproteins, Phosphorylation, Saccharomyces cerevisiae, Transcription Factors, Signal Transduction, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Saccharomyces cerevisiae Proteins, Intracellular Signaling Peptides and Proteins, Replication Protein A, Checkpoint Kinase 2
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