ArticleMolecular cancer research : MCR2012
Alkylation sensitivity screens reveal a conserved cross-species functionome.
Article in Molecular cancer research : MCR, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 39 citations in OpenAlex.
- A Novel Mitochondrial-Related Gene Signature for the Prediction of Prognosis and Therapeutic Efficacy in Lower-Grade Glioma.Biochemical genetics · 2025Article
- Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide.Neuro-oncology · 2025Article
- Functional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide.medRxiv : the preprint server for health sciences · 2024Article
- VHL suppresses UBE3B-mediated breast tumor growth and metastasis.Cell death & disease · 2024Article
- The 'Other' subfamily of HECT E3 ubiquitin ligases evaluate the tumour immune microenvironment and prognosis in patients with hepatocellular carcinoma.IET systems biology · 2024Article
- Article
- A DNA repair-independent role for alkyladenine DNA glycosylase in alkylation-induced unfolded protein response.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Isoprenylcysteine carboxyl methyltransferase is critical for glioblastoma growth and survival by activating Ras/Raf/Mek/Erk.Cancer chemotherapy and pharmacology · 2022Article
- A Potential Mechanism for Targeting Aggregates With Proteasomes and Disaggregases in Liquid Droplets.Frontiers in aging neuroscience · 2022Review
- The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc.Molecular psychiatry · 2021Article
- Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma.Cancers · 2021Article
- Imaging 6-Phosphogluconolactonase Activity in Brain TumorsFrontiers in oncology · 2021Article
- Review
- The DNA repair enzyme MUTYH potentiates cytotoxicity of the alkylating agent MNNG by interacting with abasic sites.The Journal of biological chemistry · 2020Article
- Extracellular NADScientific reports · 2020Article
- Targeting the Ubiquitin System in Glioblastoma.Frontiers in oncology · 2020Review
- Stability and sub-cellular localization of DNA polymerase β is regulated by interactions with NQO1 and XRCC1 in response to oxidative stress.Nucleic acids research · 2019Article
- C8-Substituted Imidazotetrazine Analogs Overcome Temozolomide Resistance by Inducing DNA Adducts and DNA Damage.Frontiers in oncology · 2019Article
- DNA Repair Molecular Beacon assay: a platform for real-time functional analysis of cellular DNA repair capacity.Oncotarget · 2018Article
- UBE3B Is a Calmodulin-regulated, Mitochondrion-associated E3 Ubiquitin Ligase.The Journal of biological chemistry · 2017Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
To identify genes that contribute to chemotherapy resistance in glioblastoma, we conducted a synthetic lethal screen in a chemotherapy-resistant glioblastoma-derived cell line with the clinical alkylator temozolomide (TMZ) and an siRNA library tailored toward "druggable" targets. Select DNA repair genes in the screen were validated independently, confirming the DNA glycosylases uracil-DNA glycosylase (UNG) and A/G-specific adenine DNA glycosylase (MYH) as well as methylpurine-DNA glycosylase (MPG) to be involved in the response to high dose TMZ. The involvement of UNG and MYH is likely the result of a TMZ-induced burst of reactive oxygen species. We then compared the human TMZ sensitizing genes identified in our screen with those previously identified from alkylator screens conducted in Escherichia coli and Saccharomyces cerevisiae. The conserved biologic processes across all three species compose an alkylation functionome that includes many novel proteins not previously thought to impact alkylator resistance. This high-throughput screen, validation and cross-species analysis was then followed by a mechanistic analysis of two essential nodes: base excision repair (BER) DNA glycosylases (UNG, human and mag1, S. cerevisiae) and protein modification systems, including UBE3B and ICMT in human cells or pby1, lip22, stp22 and aim22 in S. cerevisiae. The conserved processes of BER and protein modification were dual targeted and yielded additive sensitization to alkylators in S. cerevisiae. In contrast, dual targeting of BER and protein modification genes in human cells did not increase sensitivity, suggesting an epistatic relationship. Importantly, these studies provide potential new targets to overcome alkylating agent resistance.
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