N-Methyl-N′-nitro-N-nitrosoguanidine (MNNG) Triggers MSH2 and Cdt2 Protein-dependent Degradation of the Cell Cycle and Mismatch Repair (MMR) Inhibitor Protein p21Waf1/Cip1
| Autor: | Rati Fotedar, Thomas Jascur, C. Richard Boland, Serena Greene, Erin Hotchkiss |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Methylnitronitrosoguanidine Proteasome Endopeptidase Complex congenital hereditary and neonatal diseases and abnormalities DNA Repair DNA damage DNA repair Ubiquitin-Protein Ligases Protein degradation Biochemistry chemistry.chemical_compound Proliferating Cell Nuclear Antigen Humans Molecular Biology Adaptor Proteins Signal Transducing biology Ubiquitination Nuclear Proteins Cell Biology Molecular biology Chromatin digestive system diseases Proliferating cell nuclear antigen MutS Homolog 2 Protein chemistry MSH2 biology.protein DNA mismatch repair MutL Protein Homolog 1 DNA Damage HeLa Cells Nucleotide excision repair |
| Zdroj: | Journal of Biological Chemistry. 286:29531-29539 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m111.221341 |
| Popis: | p21(Waf1/Cip1) protein levels respond to DNA damage; p21 is induced after ionizing radiation, but degraded after UV. p21 degradation after UV is necessary for optimal DNA repair, presumably because p21 inhibits nucleotide excision repair by blocking proliferating cell nuclear antigen (PCNA). Because p21 also inhibits DNA mismatch repair (MMR), we investigated how p21 levels respond to DNA alkylation by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), which triggers the MMR system. We show that MNNG caused rapid degradation of p21, and this involved the ubiquitin ligase Cdt2 and the proteasome. p21 degradation further required MSH2 but not MLH1. p21 mutants that cannot bind PCNA or cannot be ubiquitinated were resistant to MNNG. MNNG induced the formation of PCNA complexes with MSH6 and Cdt2. Finally, when p21 degradation was blocked, MNNG treatment resulted in reduced recruitment of MMR proteins to chromatin. This study describes a novel pathway that removes p21 to allow cells to efficiently activate the MMR system. |
| Databáze: | OpenAIRE |
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