ArticleOncogene2016
CHK2 stability is regulated by the E3 ubiquitin ligase SIAH2.
Article in Oncogene, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 34 citations in OpenAlex.
- Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review.Biochemical Society transactions · 2021Pooled it
- Molecular landscape and clinical translation of DNA damage response alterations in solid tumors: A pan-cancer perspective on precision oncology.Neoplasia (New York, N.Y.) · 2026Review
- SIAH2-EPHB6 axis enhances filopodia formation in hepatocellular carcinoma cells by regulating RHOF.Cell & bioscience · 2026Article
- The deacetylases HDAC1/HDAC2 control JAK2Signal transduction and targeted therapy · 2025Article
- Tumour hypoxia in driving genomic instability and tumour evolution.Nature reviews. Cancer · 2025Review
- Article
- Review
- Protein degradation: expanding the toolbox to restrain cancer drug resistance.Journal of hematology & oncology · 2023Review
- SIAH2 regulates DNA end resection and replication fork recovery by promoting CtIP ubiquitination.Nucleic acids research · 2022Article
- Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation.The Journal of clinical investigation · 2021Article
- Helicobacter pylori-induced gastric cancer is orchestrated by MRCKβ-mediated Siah2 phosphorylation.Journal of biomedical science · 2021Article
- Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy.Frontiers in cell and developmental biology · 2021Review
- Review
- Article
- The Human RAD5 Homologs, HLTF and SHPRH, Have Separate Functions in DNA Damage Tolerance Dependent on The DNA Lesion Type.Biomolecules · 2020Article
- Siah2 control of T-regulatory cells limits anti-tumor immunity.Nature communications · 2020Article
- Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan.Cell research · 2016Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The serine threonine checkpoint kinase 2 (CHK2) is a critical protein involved in the DNA damage-response pathway, which is activated by phosphorylation inducing cellular response such as DNA repair, cell-cycle regulation or apoptosis. Although CHK2 activation mechanisms have been amply described, very little is known about degradation control processes. In the present study, we identify the ubiquitin E3 ligase SIAH2 as an interaction partner of CHK2, which mediates its ubiquitination and proteasomal degradation. CHK2 degradation is independent of both its activation and its kinase activity, but also of the phosphorylation in S456. We show that SIAH2-deficient cells present CHK2 accumulation together with lower ubiquitination levels. Accordingly, SIAH2 depletion by siRNA increases CHK2 levels. In response to DNA damage induced by etoposide, interaction between both proteins is disrupted, thus avoiding CHK2 degradation and promoting its stabilization. We also found that CHK2 phosphorylates SIAH2 at three residues (Thr26, Ser28 and Thr119), modifying its ability to regulate certain substrates. Cellular arrest in the G2/M phase induced by DNA damage is reverted by SIAH2 expression through the control of CHK2 levels. We observed that hypoxia decreases CHK2 levels in parallel to SIAH2 induction. Similarly, we provide evidence suggesting that resistance to apoptosis induced by genotoxic agents in cells subjected to hypoxia could be partly explained by the mutual regulation between both proteins. These results indicate that SIAH2 regulates CHK2 basal turnover, with important consequences on cell-cycle control and on the ability of hypoxia to alter the DNA damage-response pathway in cancer cells.
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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.