Tipin is required for stalled replication forks to resume DNA replication after removal of aphidicolin in Xenopus egg extracts
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Tipin and its interacting partner Tim1 (Timeless) form a complex at replication forks that plays an important role in the DNA damage checkpoint response. Here we identify Xenopus laevis Tipin as a substrate for cyclin E/cyclin-dependent kinases 2 that is phosphorylated in interphase and undergoes further phosphorylation upon entry into mitosis. During unperturbed DNA replication, the Tipin/Tim1 complex is bound to chromatin, and we were able to detect interactions between Tipin and the MCM helicase. Depletion of Tipin from Xenopus extracts did not significantly impair normal replication but substantially blocked the ability of stalled replication forks to recover after removal of a block imposed by aphidicolin. Tipin-depleted extracts also showed defects in the activation of Chk1 in response to aphidicolin, probably because of a failure to load the checkpoint mediator protein Claspin onto chromatin.
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The Tim-Tipin complex associates with ATR-Chk1 checkpoint proteins and plays an essential role in the DNA damage response.
“The circadian protein Tim (Timeless) -Tipin (Timeless-interacting protein) complex associates with ATR-Chk1 checkpoint proteins and plays an essential role in DDR as well [130–133].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [132]
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- Authors
- Errico, A., Costanzo, V., & Hunt, T.
- Affiliations
- Cancer Research UK (GB)
- Corresponding author
- Hunt, Tim
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-09-18
- Volume
- 104
- Issue
- 38
- Pages
- 14929-14934
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1975688
- OpenAlex
- W2037887345
- Cited by
- 92
- References
- 64
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 5 · 2016: 5 · 2015: 6 · 2014: 9 · 2013: 9 · 2012: 6
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK
- European Commission
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- TIPIN, TIM-1, TIMELESS, DNA replication restart, aphidicolin, MCM helicase, Chk1 activation, Claspin, DNA damage checkpoint, Xenopus egg extracts
- MeSH terms
- Checkpoint Kinase 1, Animals, Carrier Proteins, Chromatin, DNA Damage, DNA Replication, DNA-Binding Proteins, Enzyme Inhibitors, Ovum, Phosphorylation, Protein Kinases, Xenopus laevis, S Phase, Aphidicolin, Cell Cycle Proteins, Cyclin E, Xenopus Proteins, Adaptor Proteins, Signal Transducing, Cyclin-Dependent Kinase 2
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