A Shld1-Controlled POT1a Provides Support for Repression of ATR Signaling at Telomeres through RPA Exclusion
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We previously proposed that POT1 prevents ATR signaling at telomeres by excluding RPA from the single-stranded TTAGGG repeats. Here, we use a Shld1-stabilized degron-POT1a fusion (DD-POT1a) to study the telomeric ATR kinase response. In the absence of Shld1, DD-POT1a degradation resulted in rapid and reversible activation of the ATR pathway in G1 and S/G2. ATR signaling was abrogated by shRNAs to ATR and TopBP1, but shRNAs to the ATM kinase or DNA-PKcs did not affect the telomere damage response. Importantly, ATR signaling in G1 and S/G2 was reduced by shRNAs to RPA. In S/G2, RPA was readily detectable at dysfunctional telomeres, and both POT1a and POT1b were required to exclude RPA and prevent ATR activation. In G1, the accumulation of RPA at dysfunctional telomeres was strikingly less, and POT1a was sufficient to repress ATR signaling. These results support an RPA exclusion model for the repression of ATR signaling at telomeres.
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Chk2 does not appear essential for G2 arrest; damaged cells more likely progress into mitosis because of inefficient Chk1 activation and/or weak p21 induction.
“A major caveat of this interpretation is that Chk2 does not seem to play an essential role in G2 arrest 84,85,72 and it is more likely that damaged cells progress into mitosis due to inefficient Chk1 activation 86 and/or lack of robust p21 induction.”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [86]
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- Authors
- Gong, Y., & de Lange, T.
- Affiliations
- Rockefeller University (US)
- ORCID
- Gong, Yi
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 40
- Issue
- 3
- Pages
- 377-387
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3111920
- OpenAlex
- W2114697209
- Cited by
- 102
- References
- 32
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 9 · 2020: 6 · 2019: 6 · 2018: 9 · 2017: 9 · 2016: 7 · 2015: 4 · 2014: 9 · 2013: 9 · 2012: 5
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Cancer Society
- National Institutes of Health (DP1OD000379)
- National Institute on Aging (R56AG016642, AG016642, R01AG016642)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- ATR signaling, telomeres, TopBP1, protein degradation, G1 phase, S/G2 phase, telomere dysfunction
- MeSH terms
- Shelterin Complex, Animals, DNA Damage, DNA-Binding Proteins, Enzyme Activation, Humans, Interphase, Morpholines, Repressor Proteins, Signal Transduction, Telomere, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Cytoprotection, Telomere-Binding Proteins, RNA, Small Interfering, Mice, Replication Protein A, HEK293 Cells, Ataxia Telangiectasia Mutated Proteins
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