TopBP1 and DNA polymerase-α directly recruit the 9-1-1 complex to stalled DNA replication forks
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TopBP1 and the Rad9–Rad1–Hus1 (9-1-1) complex activate the ataxia telangiectasia mutated and Rad3-related (ATR) protein kinase at stalled replication forks. ATR is recruited to stalled forks through its binding partner, ATR-interacting protein (ATRIP); however, it is unclear how TopBP1 and 9-1-1 are recruited so that they may join ATR–ATRIP and initiate signaling. In this study, we use Xenopus laevis egg extracts to determine the requirements for 9-1-1 loading. We show that TopBP1 is required for the recruitment of both 9-1-1 and DNA polymerase (pol)-α to sites of replication stress. Furthermore, we show that pol-α is also directly required for Rad9 loading. Our study identifies an assembly pathway, which is controlled by TopBP1 and includes pol-α, that mediates the loading of the 9-1-1 complex onto stalled replication forks. These findings clarify early events in the assembly of checkpoint signaling complexes on DNA and identify TopBP1 as a critical sensor of replication stress.
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TopBP1 is required for recruiting ATR and the 9-1-1 complex onto genotoxin-damaged chromatin or stalled replication forks in Xenopus egg extracts and human cell lines.
“TopBP1 is required for the recruitment of ATR and the 9-1-1 complex onto genotoxin-damaged chromatin or stalled replication forks in Xenopus egg extracts and human cell lines [121–123].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [122]
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References 51 · Cited by 107
- Authors
- Yan, S., & Michael, W. M.
- Affiliations
- Harvard University (US)
- Corresponding author
- Michael, W. Matthew
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2009-03-16
- Volume
- 184
- Issue
- 6
- Pages
- 793-804
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2699152
- OpenAlex
- W2109910662
- Cited by
- 107
- References
- 51
- Citations by year
- 2026: 4 · 2024: 5 · 2023: 11 · 2022: 4 · 2021: 5 · 2020: 1 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 6 · 2014: 8 · 2013: 14 · 2012: 2
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM 067735, R01GM067735)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- TopBP1, 9-1-1 complex, DNA polymerase alpha, replication fork stalling, replication stress, ATR signaling, ATRIP, DNA damage checkpoint, Xenopus egg extracts
- MeSH terms
- Animals, Carrier Proteins, Chromatin, Chromosomal Proteins, Non-Histone, Cloning, Molecular, DNA, DNA Polymerase I, DNA Replication, DNA-Binding Proteins, Stress, Physiological, Time Factors, Xenopus laevis, Signal Transduction, Mutagenesis, Site-Directed, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Xenopus Proteins, Multiprotein Complexes, Ataxia Telangiectasia Mutated Proteins
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