Unwind and slow down: checkpoint activation by helicase and polymerase uncoupling: Figure 1.
Open accessAbstract
Phosphoinositide 3-kinase related protein kinases (PIKK) including ataxia-telangiectasia mutated (ATM), DNAdependent protein kinase (DNA-PK), and ATM and Rad3-related (ATR) coordinate cellular responses to DNA damage.DNA-PK and ATM are primarily activated by double-strand breaks.The ATR kinase, in contrast, responds to numerous forms of genotoxic stress including intrastrand cross-links, oxidative damage, and polymerase toxins.At first glance, the disparate DNA structures that activate ATR impose a difficult biochemical challenge for damage sensing.However, recent data indicate that one DNA structure-single-stranded DNA (ssDNA) coated with a single-stranded DNA-binding protein (RPA)-is a common intermediate to activate ATR signaling in response to all of these genotoxic lesions.In this issue, Cimprich and colleagues (Byun et al. 2005) define how DNA damage and polymerase toxins use a common mechanism to generate the RPA-ssDNA needed to activate ATR.The method is the decoupling of helicase and polymerase activities at a replication fork.
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Stalled replication forks are processed to long ssDNA, where RPA binds and initiates recruitment of DDR proteins including ATRIP-ATR, TopBP1, MRE11, Rad50, Rad17, and the 9-1-1 complex.
“These breaks are processed to long ssDNA, where RPA binds and initiates the recruitment of a complex array of DNA damage response (DDR) proteins, including ATRIP-ATR complex, TopBP1, MRE11, Rad50, Rad17, and 9-1-1 complex [17–19].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [17]
During S phase, replication forks encounter CPD and 6-4PP lesions that provoke stalling of replication forks at single-strand breaks.
“In addition, during S phase, replication forks encounter the CPD and 6-4PP lesions that provoke stalling of the replication forks at the single-strand breaks (SSBs).”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [17]
DNA damage and replication intermediates increase DNA unwinding, leading to RPA-coated ssDNA accumulation that recruits ATR.
“It has been shown that DNA damage and replication intermediates increase the unwinding of DNA, leading to the accumulation of RPA-coated ss-DNA, which recruits ATR [15, 16].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [15]
ATR is the main sensor of single-stranded DNA breaks caused by UV damage and replication stress.
“ATR is the primary sensor of single-stranded (ssDNA) breaks (SSB) caused by UV damage and replication stress.”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [15]
After UV irradiation, RPA-coated single-stranded DNA recruits ATR to the UV damage site.
“It has been shown that in response to UV irradiation, RPA-coated single-stranded DNA (ssDNA) recruits ATR to the UV damage site [15, 16].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [15]
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References 50 · Cited by 84
- Authors
- Cortez, D.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Cortez, David
- ORCID
- Cortez, David
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2005-05-01
- Volume
- 19
- Issue
- 9
- Pages
- 1007-1012
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1360198
- OpenAlex
- W2134049133
- Cited by
- 84
- References
- 50
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 3 · 2014: 6 · 2013: 6 · 2012: 4
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Pew Charitable Trusts
- National Institutes of Health
- National Cancer Institute (R01CA102729, K01CA093701)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- ATR signaling, DNA damage checkpoint, replication fork, RPA, single-stranded DNA, genotoxic stress, DNA damage recognition, PIKK kinases
- MeSH terms
- DNA Damage, DNA-Directed DNA Polymerase, DNA Helicases, DNA-Binding Proteins, DNA, Single-Stranded, Humans, Signal Transduction, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Genes, cdc, Replication Protein A, Ataxia Telangiectasia Mutated Proteins
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