Roles of N-Myc and STAT interactor in cancer: From initiation to dissemination

Pruitt, Hawley C.; Devine, Daniel J.; Samant, Rajeev S.

NMI interacts with multiple proteins that are essential for different steps in the DNA damage sensing and repair pathways. BRCA1 is essential for maintaining genomic stability because of its roles in DNA double strand break repair through homologous recombination. 10 Naturally occurring DNA damage is identified and repaired through BRCA1 function, thus women with germline mutations in either BRCA1 or BRCA2 have a 50-80% lifetime risk of developing breast cancer. 10 Before DNA repair pathways can be activated, areas of damaged DNA need to be detected. NMI may be involved in sensing DNA damage via its interaction with Tip60, a histone acetyltransferase that is activated by radiation-induced, double-stranded DNA breaks. 11 Interaction of H3K9 trimethylated histones and Tip60's chromodomain recruits ATM kinase to the site of double stranded breaks. Acetylation of ATM by Tip60 at lysine 3016 changes the conformation of ATM to allow substrate proteins to access the kinase Figure 2 . NMI influences cancer initiation. NMI together with BRCA1 sequesters MYC, thereby reducing downstream hTERT gene transcription and inhibiting immortalization of cells during early stages of carcinogenesis. Accumulation of mutations due to DNA damage leads to the transformation of cells. Ionizing radiation and alkylating agents up-regulate NMI expression and trigger the DNA damage response. Through its interaction with the histone acetyltransferase, Tip60, and tumor suppressor, ARF, NMI could play a role in ATM and p53-dependent DNA damage responses. The interaction between NMI, ARF and Tip60 may be in a complex to facilitate activation of ATM at sites of DNA damage or independent of each other. Stabilization of ARF by NMI blocks MDM2-mediated p53 degradation and promotes G2 cell cycle arrest. In addition, NMI may assist Tip60 in its independent inhibition of MDM2 leading to p53 stabilization. However, in contrast, NMI binds STAT1 in glioma cells leading to inhibition of G0/G1 cell cycle arrest. Lastly, NMI facilitates autophagic cell death in response to DNA damage by activating GSK3b and subsequently inhibiting the mTOR pathway-a pathway that blocks autophagy. Expression of DRAM1, a protein essential for the fusing of autophagosomes with lysosomes, positively correlated with NMI levels in breast cancer patients. The dotted connectors indicate possible interactions whereas solid connectors are supported by at least one peer-reviewed publication.