ArticlePLoS genetics2012
Chemical genetics reveals a specific requirement for Cdk2 activity in the DNA damage response and identifies Nbs1 as a Cdk2 substrate in human cells.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 60 citations in OpenAlex.
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- Abemaciclib Inhibits Retinoblastoma Tumor Growth by Targeting CDK1/2.Investigative ophthalmology & visual science · 2026Article
- REV7-p53 interaction inhibits ATM-mediated DNA damage signaling.Cell cycle (Georgetown, Tex.) · 2024Article
- CDK2 regulates collapsed replication fork repair in CCNE1-amplified ovarian cancer cells via homologous recombination.NAR cancer · 2023Article
- Maintaining Genome Integrity: Protein Kinases and Phosphatases Orchestrate the Balancing Act of DNA Double-Strand Breaks Repair in Cancer.International journal of molecular sciences · 2023Review
- Article
- Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition.NPJ breast cancer · 2021Article
- CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis.Cancer research · 2021Article
- In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer.Scientific reports · 2021Article
- Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action.International journal of molecular sciences · 2021Review
- Identification of PIM1 substrates reveals a role for NDRG1 phosphorylation in prostate cancer cellular migration and invasion.Communications biology · 2021Article
- Article
- SCFCell death & disease · 2020Article
- Rapid block of pre-mRNA splicing by chemical inhibition of analog-sensitive CRK9 in Trypanosoma brucei.Molecular microbiology · 2020Article
- A novel landscape of nuclear human CDK2 substrates revealed by in situ phosphorylation.Science advances · 2020Article
- CRIF1 as a potential target to improve the radiosensitivity of osteosarcoma.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- How Surrogate and Chemical Genetics in Model Organisms Can Suggest Therapies for Human Genetic Diseases.Genetics · 2018Review
- Direct Substrate Identification with an Analog Sensitive (AS) Viral Cyclin-Dependent Kinase (v-Cdk).ACS chemical biology · 2018Article
- Structure-based discovery of cyclin-dependent protein kinase inhibitors.Essays in biochemistry · 2017Review
- Cdk2 strengthens the intra-S checkpoint and counteracts cell cycle exit induced by DNA damage.Scientific reports · 2017Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
The cyclin-dependent kinases (CDKs) that promote cell-cycle progression are targets for negative regulation by signals from damaged or unreplicated DNA, but also play active roles in response to DNA lesions. The requirement for activity in the face of DNA damage implies that there are mechanisms to insulate certain CDKs from checkpoint inhibition. It remains difficult, however, to assign precise functions to specific CDKs in protecting genomic integrity. In mammals, Cdk2 is active throughout S and G2 phases, but Cdk2 protein is dispensable for survival, owing to compensation by other CDKs. That plasticity obscured a requirement for Cdk2 activity in proliferation of human cells, which we uncovered by replacement of wild-type Cdk2 with a mutant version sensitized to inhibition by bulky adenine analogs. Here we show that transient, selective inhibition of analog-sensitive (AS) Cdk2 after exposure to ionizing radiation (IR) enhances cell-killing. In extracts supplemented with an ATP analog used preferentially by AS kinases, Cdk2(as) phosphorylated the Nijmegen Breakage Syndrome gene product Nbs1-a component of the conserved Mre11-Rad50-Nbs1 complex required for normal DNA damage repair and checkpoint signaling-dependent on a consensus CDK recognition site at Ser432. In vivo, selective inhibition of Cdk2 delayed and diminished Nbs1-Ser432 phosphorylation during S phase, and mutation of Ser432 to Ala or Asp increased IR-sensitivity. Therefore, by chemical genetics, we uncovered both a non-redundant requirement for Cdk2 activity in response to DNA damage and a specific target of Cdk2 within the DNA repair machinery.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.