NAD in cancer cells

Nicotinamide mononucleotide adenylyltransferases (NMNATs)

Nicotinamide mononucleotide adenylyltransferases (NMNATs) have long been known as key enzymes in NAD biosynthesis in all living organisms. They catalyze the conversion of nicotinamide mononucleotide (NMN) and ATP to NAD. The major function of  NAD is to serve as an electron carrier, but it also participates as a substrate in a number of signaling pathways, including poly(ADP-ribosyl)ation (PARylation) catalyzed by a family of poly(ADP-ribose) polymerase (PARP) enzymes. PARylation has been implicated in a wide range of biological processes such as DNA repair, maintenance of genomic stability, replication, proliferation and cell death. Both PARP-1 and NMNAT-1 are localized in the nucleus. A novel finding is that PARP-1 recruits NMNAT-1 to promoters to produce NAD to support PARP-1 catalytic activity. Furthermore, NMNAT-1 itself also may modulate the activity of PARP-1 independently of NAD-production, but data on the relationship between NMNAT-1 and PARP activity are controversial. PARP inhibitors are used in clinical trials of cancer chemotherapy alone and in combination with DNA-damaging agents. It is known that NMNAT-1 is expressed in cancer cells at relatively low levels. The available information about the possible role of NMNAT-1 in tumors is limited to lung tumor cell lines, where sensititivity to doxorubicin was significantly higher in NMNAT-1 silenced cells. Silencing of NMNAT-1 was reported to delay the repair of single strand DNA breaks. However, the physiological role of PARP-1 – NMNAT-1 interactions in cell death with special regard to chemotherapeutics-induced death of tumor cells has not yet been investigated.