A Role for the MRN Complex in ATR Activation via TOPBP1 Recruitment
Open accessAbstract
The MRN (MRE11-RAD50-NBS1) complex has been implicated in many aspects of the DNA damage response. It has key roles in sensing and processing DNA double-strand breaks, as well as in activation of ATM (ataxia telangiectasia mutated). We reveal a function for MRN in ATR (ATM- and RAD3-related) activation by using defined ATR-activating DNA structures in Xenopus egg extracts. Strikingly, we demonstrate that MRN is required for recruitment of TOPBP1 to an ATR-activating structure that contains a single-stranded DNA (ssDNA) and a double-stranded DNA (dsDNA) junction and that this recruitment is necessary for phosphorylation of CHK1. We also show that the 911 (RAD9-RAD1-HUS1) complex is not required for TOPBP1 recruitment but is essential for TOPBP1 function. Thus, whereas MRN is required for TOPBP1 recruitment at an ssDNA-to-dsDNA junction, 911 is required for TOPBP1 "activation." These findings provide molecular insights into how ATR is activated.
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The MRN complex is needed to activate ATM-dependent DDR after double-strand breaks and ATR-dependent DDR after stalled replication forks.
“The MRN complex is required for the activation of ATM and ATR-dependent DDR pathways in response to DSBs and stalled DNA replication forks, respectively [57, 125, 218].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [125]
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- Authors
- Duursma, A. M., Driscoll, R., Elias, J. E., & Cimprich, K. A.
- Affiliations
- Stanford University (US)
- Corresponding author
- Cimprich, Karlene A.
- ORCID
- Cimprich, Karlene A.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 50
- Issue
- 1
- Pages
- 116-122
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3669687
- OpenAlex
- W1993580403
- Cited by
- 153
- References
- 36
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 13 · 2020: 11 · 2019: 11 · 2018: 9 · 2017: 14 · 2016: 19 · 2015: 19 · 2014: 19 · 2013: 7
- FWCI
- 9.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Environmental Health Sciences (ES016486, R01ES016486)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- MRN complex, TopBP1, Chk1 phosphorylation, single-stranded DNA, DNA damage response, DNA double-strand breaks, ATM, Xenopus egg extracts
- MeSH terms
- Checkpoint Kinase 1, MRE11 Homologue Protein, Animals, Binding Sites, Carrier Proteins, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, DNA, Single-Stranded, Enzyme Activation, Humans, Nucleic Acid Conformation, Phosphorylation, Protein Binding, Protein Kinases, Transfection, Xenopus laevis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Xenopus Proteins, RNA Interference, DNA Repair Enzymes, Cell Line, Tumor, Multiprotein Complexes, Ataxia Telangiectasia Mutated Proteins
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