Abstract
Multiple endocrine neoplasia type 1 is a familial cancer syndrome resulting from loss-of-function mutations in the MEN1 gene. We previously identified the tumor suppressor MEN1 as a gene required for oncogene-induced senescence in melanocytes, raising the possibility that MEN1 is a melanoma tumor suppressor. Here we show that MEN1 expression is lost in a high percentage of human melanomas and melanoma cell lines. We find that melanocytes depleted of MEN1 are deficient in homologous recombination (HR)-directed DNA repair, which is accompanied by increased nonhomologous end-joining activity. Following DNA damage, MEN1 levels increase as a result of phosphorylation by the DNA damage kinase ATM/ATR. Most importantly, we show that MEN1 functions by directly stimulating the transcription of several genes, including BRCA1, RAD51, and RAD51AP1, that encode proteins involved in HR. MEN1 and its coactivator, the mixed-lineage leukemia histone methyltransferase, are recruited to the BRCA1, RAD51, and RAD51AP1 promoters by estrogen receptor 1, resulting in increased histone H3-lysine 4 trimethylation and transcription. Collectively, our results indicate that MEN1 is a melanoma tumor suppressor that functions by stimulating the transcription of genes involved in HR-directed DNA repair.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Ataxia Telangiectasia Mutated Proteins
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BRCA1 Protein / genetics
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line
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Cell Line, Tumor
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DNA Breaks, Double-Stranded
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DNA Damage / genetics
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DNA End-Joining Repair / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism
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Gene Expression Regulation
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Gene Expression Regulation, Neoplastic
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Histone-Lysine N-Methyltransferase
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Humans
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Melanoma / genetics*
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / metabolism
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Phosphorylation
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Promoter Regions, Genetic
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA-Binding Proteins
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Rad51 Recombinase / genetics
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Rad51 Recombinase / metabolism
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Recombinational DNA Repair / genetics*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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BRCA1 Protein
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BRCA1 protein, human
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Cell Cycle Proteins
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DNA-Binding Proteins
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ESR1 protein, human
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Estrogen Receptor alpha
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KMT2A protein, human
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MEN1 protein, human
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Proto-Oncogene Proteins
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RAD51AP1 protein, human
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RNA-Binding Proteins
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Tumor Suppressor Proteins
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Myeloid-Lymphoid Leukemia Protein
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Histone-Lysine N-Methyltransferase
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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RAD51 protein, human
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Rad51 Recombinase