ArticleProceedings of the National Academy of Sciences of the United States of America2012
Regulation of oxidative DNA damage repair by DNA polymerase λ and MutYH by cross-talk of phosphorylation and ubiquitination.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 73 citations in OpenAlex.
- The polymerase milieu of human papillomavirus.Journal of virology · 2026Review
- DNA repair under heat: DNA polymerase λ modulates heat stress-induced mutagenesis in plants.The Plant cell · 2026Article
- PARG regulates the proteasomal degradation of TARG1.Cell reports · 2026Article
- E3 ligases: a ubiquitous link between DNA repair, DNA replication and human disease.The Biochemical journal · 2024Review
- HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways.Cell reports · 2023Article
- The ubiquitin-like modifier FAT10 covalently modifies HUWE1 and strengthens the interaction of AMBRA1 and HUWE1.PloS one · 2023Article
- Comparison of the Medical Uses and Cellular Effects of High and Low Linear Energy Transfer Radiation.Toxics · 2022Review
- The giant E3 ligase HUWE1 is linked to tumorigenesis, spermatogenesis, intellectual disability, and inflammatory diseases.Frontiers in cellular and infection microbiology · 2022Review
- Review
- Targeting of the E3 ubiquitin-protein ligase HUWE1 impairs DNA repair capacity and tumor growth in preclinical multiple myeloma models.Scientific reports · 2020Article
- The structure and regulation of the E3 ubiquitin ligase HUWE1 and its biological functions in cancer.Investigational new drugs · 2020Review
- When you're strange: Unusual features of the MUTYH glycosylase and implications in cancer.DNA repair · 2019Review
- Deployment of DNA polymerases beta and lambda in single-nucleotide and multinucleotide pathways of mammalian base excision DNA repair.DNA repair · 2019Article
- Ubiquitination by HUWE1 in tumorigenesis and beyond.Journal of biomedical science · 2018Review
- Oxidative and genotoxic damages in plants in response to heavy metal stress and maintenance of genome stability.Plant signaling & behavior · 2018Article
- Article
- HUWE1 controls the development of non-small cell lung cancer through down-regulation of p53.Theranostics · 2018Article
- Impaired oxidative stress response characterizes HUWE1-promoted X-linked intellectual disability.Scientific reports · 2017Article
- Noncatalytic, N-terminal Domains of DNA Polymerase Lambda Affect Its Cellular Localization and DNA Damage Response.Chemical research in toxicology · 2017Article
- Ubiquitylation-dependent regulation of NEIL1 by Mule and TRIM26 is required for the cellular DNA damage response.Nucleic acids research · 2017Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
It is of pivotal importance for genome stability that repair DNA polymerases (Pols), such as Pols λ and β, which all exhibit considerably reduced fidelity when replicating undamaged DNA, are tightly regulated, because their misregulation could lead to mutagenesis. Recently, we found that the correct repair of the abundant and highly miscoding oxidative DNA lesion 7,8-dihydro-8-oxo-2'-deoxyguanine (8-oxo-G) is performed by an accurate repair pathway that is coordinated by the MutY glycosylase homologue (MutYH) and Pol λ in vitro and in vivo. Pol λ is phosphorylated by Cdk2/cyclinA in late S and G2 phases of the cell cycle, promoting Pol λ stability by preventing it from being targeted for proteasomal degradation by ubiquitination. However, it has remained a mystery how the levels of Pol λ are controlled, how phosphorylation promotes its stability, and how the engagement of Pol λ in active repair complexes is coordinated. Here, we show that the E3 ligase Mule mediates the degradation of Pol λ and that the control of Pol λ levels by Mule has functional consequences for the ability of mammalian cells to deal with 8-oxo-G lesions. Furthermore, we demonstrate that phosphorylation of Pol λ by Cdk2/cyclinA counteracts its Mule-mediated degradation by promoting recruitment of Pol λ to chromatin into active 8-oxo-G repair complexes through an increase in Pol λ's affinity to chromatin-bound MutYH. Finally, MutYH appears to promote the stability of Pol λ by binding it to chromatin. In contrast, Pol λ not engaged in active repair on chromatin is subject for proteasomal degradation.
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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.