Potential roles of 3′-5′ exonuclease activity of NM23-H1 in DNA repair and malignant progression

NM23-H1 is a metastasis suppressor protein that exhibits 3'-5' exonuclease activity in vitro. As 3'-5' exonucleases are generally required for maintenance of genome integrity, this activity represents a plausible candidate mediator of the metastasis suppressor properties of the NM23-H1 molecule. Consistent with an antimutator function, ablation of the yeast NM23 homolog, YNK1, results in increased mutation rates following exposure to UV irradiation and exposure to the DNA damaging agents etoposide, cisplatin, and MMS. In human cells, a DNA repair function is further suggested by increased NM23-H1 expression and nuclear translocation following DNA damage. Also, forced expression of NM23-H1 in NM23-deficient and metastatic cell lines results in coordinate downregulation of multiple DNA repair genes, possibly reflecting genomic instability associated with the NM23-deficient state. To assess the relevance of the 3'-5' exonuclease activity of NM23-H1 to its antimutator and metastasis suppressor functions, a panel of mutants harboring defects in the 3'-5' exonuclease and other enzymatic activities of the molecule (NDPK, histidine kinase) have been expressed by stable transfection in the melanoma cell line, 1205Lu. Pilot in vivo metastasis assays indicate 1205Lu cells are highly responsive to the metastasis suppressor effects of NM23-H1, thus providing a valuable model for measuring the extent to which the nuclease function opposes metastasis and metastatic progression.