TopBP1 and DNA polymerase alpha-mediated recruitment of the 9-1-1 complex to stalled replication forks: implications for a replication restart-based mechanism for ATR checkpoint activation
Open accessAbstract
Upon sensing DNA damage or replication stress, cells trigger checkpoint response pathways that control cell cycle progression and maintain genomic stability. A variety of DNA lesions can activate the ATR (ATM and Rad3-related) protein kinase, which phosphorylates its critical substrate Chk1 to relay the checkpoint signal. ATR activation requires several factors, including the BRCT repeat-containing TopBP1 protein and the 9-1-1 clamp protein. Here, we summarize recent advances in understanding the multiple roles played by TopBP1 in ATR activation at stalled replication forks. We review recent studies showing that TopBP1 controls the loading of 9-1-1 onto stalled replication forks via a pathway that also requires DNA polymerase alpha (pol alpha). Based on these recent studies, we present a revised model for ATR activation, and speculate that TopBP1-mediated recruitment of pol alpha and 9-1-1 may couple checkpoint activation to replication restart, when DNA synthesis is blocked on the leading strand of a replication fork. Lastly, we present a new experiment that examines how TopBP1 binds to stalled replication forks, and we identify important new questions that our recent studies have raised regarding how stalled replication forks are sensed by the ATR checkpoint pathway.
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In UVC-irradiated XP-C cells, ATR activation might be triggered by accumulation of ssDNA gaps during replication, leading to mild and temporary G2-phase arrest.
“In UVC-irradiated XP-C cells, ATR activation might be triggered by the accumulation of ssDNA gaps during DNA replication, leading to a mild and temporary G2-phase arrest, in agreement with previous work [18,19,24,50]”
From Gap-filling and bypass at the replication fork are both active mechanisms for tolerance of low-dose ultraviolet-induced DNA damage in the human genome (2014) · cites this paper as [50]
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Self-citation
- Authors
- Yan, S., & Michael, W. M.
- Affiliations
- Harvard University (US)
- Corresponding author
- Michael, W. Matthew
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2009-09-15
- Volume
- 8
- Issue
- 18
- Pages
- 2877-2884
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W2038245737
- Cited by
- 72
- References
- 0
- Citations by year
- 2025: 2 · 2024: 6 · 2023: 11 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 5 · 2016: 2 · 2015: 6 · 2014: 7 · 2013: 8 · 2012: 4
- FWCI
- 0.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- 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 › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- TopBP1, DNA polymerase alpha, stalled replication forks, replication restart, replication stress, DNA damage response, Chk1 phosphorylation, BRCT domain, checkpoint signaling
- MeSH terms
- Animals, Carrier Proteins, DNA Polymerase I, DNA Replication, DNA-Binding Proteins, Humans, Nuclear Proteins, Nucleic Acid Conformation, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins
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