1. The NAD+ Synthesis Enzyme Nicotinamide Mononucleotide Adenylyltransferase (NMNAT1) Regulates Ribosomal RNA Transcription*
- Author
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Neha Kabra, Tanjing Song, Lihong Chen, Eric B. Haura, John M. Koomen, Jiandong Chen, and Leixiang Yang
- Subjects
Transcription, Genetic ,DNA damage ,Gene Dosage ,Repressor ,Down-Regulation ,Biochemistry ,Sirtuin 1 ,Transcription (biology) ,NMNAT1 ,Cell Line, Tumor ,Humans ,Gene Regulation ,Gene Silencing ,Nicotinamide-Nucleotide Adenylyltransferase ,Molecular Biology ,Nicotinamide-nucleotide adenylyltransferase ,biology ,Cell Death ,Nuclear Proteins ,RNA-Binding Proteins ,Acetylation ,Cell Biology ,Methyltransferases ,NAD ,Molecular biology ,RRNA transcription ,Gene Expression Regulation, Neoplastic ,Glucose ,Doxorubicin ,RNA, Ribosomal ,Gene Knockdown Techniques ,biology.protein ,NAD+ kinase ,Cell Nucleolus ,DNA Damage ,Protein Binding - Abstract
The chromosomal region encoding the nuclear NAD(+) synthesis enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT1) is frequently deleted in human cancer. We describe evidence that NMNAT1 interacts with the nucleolar repressor protein nucleomethylin and is involved in regulating rRNA transcription. NMNAT1 binds to nucleomethylin and is recruited into a ternary complex containing the NAD(+)-dependent deacetylase SirT1. NMNAT1 expression stimulates the deacetylase function of SirT1. Knockdown of NMNAT1 enhances rRNA transcription and promotes cell death after nutrient deprivation. Furthermore, NMNAT1 expression is induced by DNA damage and plays a role in preventing cell death after damage. Heterozygous deletion of NMNAT1 in lung tumor cell lines correlates with low expression level and increased sensitivity to DNA damage. These results suggest that NMNAT1 deletion in tumors may contribute to transformation by increasing rRNA synthesis, but may also increase sensitivity to nutrient stress and DNA damage.
- Published
- 2013