ArticleProceedings of the National Academy of Sciences of the United States of America2009
Two proteolytic pathways regulate DNA repair by cotargeting the Mgt1 alkylguanine transferase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 81 citations in OpenAlex.
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- The DNA Alkyltransferase Family of DNA Repair Proteins: Common Mechanisms, Diverse Functions.International journal of molecular sciences · 2023Review
- Crystal structure of the Ate1 arginyl-tRNA-protein transferase and arginylation of N-degron substrates.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
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- Repurposing the Damage Repair Protein Methyl Guanine Methyl Transferase as a Ligand Inducible Fusion Degron.ACS chemical biology · 2022Article
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- Integrative genomic analysis identifies associations of molecular alterations to APOBEC and BRCA1/2 mutational signatures in breast cancer.Molecular genetics & genomic medicine · 2019Article
- Temozolomide-perillyl alcohol conjugate downregulates OCell death & disease · 2018Article
- Every OGT Is Illuminated … by Fluorescent and Synchrotron Lights.International journal of molecular sciences · 2017Review
- Sequestration from Protease Adaptor Confers Differential Stability to Protease Substrate.Molecular cell · 2017Article
- Interactome Analysis Reveals a Novel Role for RAD6 in the Regulation of Proteasome Activity and Localization in Response to DNA Damage.Molecular and cellular biology · 2017Article
- Analyzing N-terminal Arginylation through the Use of Peptide Arrays and Degradation Assays.The Journal of biological chemistry · 2016Article
- Physiological functions and clinical implications of the N-end rule pathway.Frontiers of medicine · 2016Review
- Degradation of Serotonin N-Acetyltransferase, a Circadian Regulator, by the N-end Rule Pathway.The Journal of biological chemistry · 2016Article
- The Deubiquitinase USP47 Stabilizes MAPK by Counteracting the Function of the N-end Rule ligase POE/UBR4 in Drosophila.PLoS biology · 2016Article
- Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung.Cancer research · 2015Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
O(6)-methylguanine (O(6)meG) and related modifications of guanine in double-stranded DNA are functionally severe lesions that can be produced by many alkylating agents, including N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a potent carcinogen. O(6)meG is repaired through its demethylation by the O(6)-alkylguanine-DNA alkyltransferase (AGT). This protein is called Mgmt (or MGMT) in mammals and Mgt1 in the yeast Saccharomyces cerevisiae. AGT proteins remove methyl and other alkyl groups from an alkylated O(6) in guanine by transferring the adduct to an active-site cysteine residue. The resulting S-alkyl-Cys of AGT is not restored back to Cys, so repair proteins of this kind can act only once. We report here that S. cerevisiae Mgt1 is cotargeted for degradation, through a degron near its N terminus, by 2 ubiquitin-mediated proteolytic systems, the Ubr1/Rad6-dependent N-end rule pathway and the Ufd4/Ubc4-dependent ubiquitin fusion degradation (UFD) pathway. The cotargeting of Mgt1 by these pathways is synergistic, in that it increases not only the yield of polyubiquitylated Mgt1, but also the processivity of polyubiquitylation. The N-end rule and UFD pathways comediate both the constitutive and MNNG-accelerated degradation of Mgt1. Yeast cells lacking the Ubr1 and Ufd4 ubiquitin ligases were hyperresistant to MNNG but hypersensitive to the toxicity of overexpressed Mgt1. We consider ramifications of this discovery for the control of DNA repair and mechanisms of substrate targeting by the ubiquitin system.
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