The identification of translesion DNA synthesis regulators: Inhibitors in the spotlight
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Over the past half-century, we have become increasingly aware of the ubiquity of DNA damage. Under the constant exposure to exogenous and endogenous genomic stress, cells must attempt to replicate damaged DNA. The encounter of replication forks with DNA lesions triggers several cellular responses, including the activation of translesion DNA synthesis (TLS), which largely depends upon specialized DNA polymerases with flexible active sites capable of accommodating bulky DNA lesions. A detrimental aspect of TLS is its intrinsic mutagenic nature, and thus the activity of the TLS polymerases must ideally be restricted to synthesis on damaged DNA templates. Despite their potential clinical importance in chemotherapy, TLS inhibitors have been difficult to identify since a direct assay designed to quantify genomic TLS events is still unavailable. Herein we discuss the methods that have been used to validate TLS inhibitors such as USP1, p21 and Spartan, highlighting research that has revealed their contribution to the control of DNA synthesis on damaged and undamaged templates.
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The encounter of a replication fork with a DNA lesion must promote rapid CRL4Cdt2-dependent proteolysis of p21 to allow utilization of damaged DNA as templates for DNA synthesis by specialized DNA polymerases.
“the encounter of a replication fork with a DNA lesion must promote the rapid CRL4Cdt2-dependent proteolysis of p21 to allow the utilization of damaged DNA as templates for DNA synthesis by specialized DNA polymerases [77]”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [77]
On undamaged DNA, p21 displaces specialized DNA polymerases, favoring DNA replication by pol δ and pol ε.
“While on undamaged DNA, p21 displaces specialized DNA polymerases favoring DNA replication by pol δ and pol ε”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [77]
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CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication
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- Authors
- Bertolin, A. P., Mansilla, S. F., & Gottifredi, V.
- Affiliations
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Corresponding author
- Gottifredi, V.
- Venue
- DNA Repair
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 32
- Pages
- 158-164
- ISSN
- 1568-7856 (ISSN-L)
- 1568-7864
- PMC
- PMC4522396
- OpenAlex
- W257383267
- Cited by
- 30
- References
- 61
- Citations by year
- 2025: 4 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 2 · 2017: 6 · 2016: 3
- FWCI
- 1.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- DNA repair (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Conicet (submittedVersion, cc-by-nc-sa)
- Funders
- Consejo Nacional de Investigaciones Científicas y Técnicas
- National Institutes of Health
- Agencia Nacional de Promoción Científica y Tecnológica (CONICET)
- Fogarty International Center (R03TW008924)
- 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
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- translesion synthesis, DNA polymerase, DNA damage, replication fork stalling, mutagenesis, USP1, p21, Spartans, DNA replication
- MeSH terms
- DNA, DNA Damage, DNA-Directed DNA Polymerase, DNA Repair, DNA Replication, DNA-Binding Proteins, Gene Expression Regulation, Humans, Mutagenesis, Proliferating Cell Nuclear Antigen, Cyclin-Dependent Kinase Inhibitor p21, Ubiquitin-Specific Proteases
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