Abstract 1445: The metastasis suppressor NM23-H1 promotes genomic stability through its 3’-5’ exonuclease and nucleoside diphosphate kinase activities following UV irradiation

NM23-H1 is a metastasis suppressor whose reduced expression is associated with aggressive forms of melanoma, hepatoma, and carcinomas of the breast, stomach and colon. The current study has identified NM23-H1 (termed H1 isoform in human, M1 in mouse) and two of its attendant enzymatic activities, the 3’-5’ exonuclease and nucleoside diphosphate kinase (NDPK), as novel participants in the response to UV-induced DNA damage. Kinetics of repair for total DNA polymerase-blocking lesions and nucleotide excision pathway-mediated repair of 6-4 photoproducts were significantly compromised in different cellular settings of NM23-H1-deficiency. These included the human melanoma cell line WM793 and embryo fibroblasts (MEFs) derived from mouse strains rendered deficient in either NM23-M1 alone or both the M1 and M2 isoforms in tandem. The NDPK activity of NM23-H1 was critical for early repair of both polychromatic UVB/UVA (275-400 nm)- and UVC (254 nm)-induced DNA damage. Elevated rates of spontaneous and UV-induced mutations were observed in WM793 cells and NM23-deficient MEFs. The mutational spectra reflected aberrant repair of 6-4 photoproducts and oxidatively-induced DNA damage, with the 3’-5’ exonuclease being the principal enzymatic activity required to reduce UV-induced mutagenesis. This study has provided the first evidence for an essential role of mammalian NM23 isoforms in maintaining genomic stability. This novel anti-mutator function appears relevant not only to the metastasis suppressor activity of NM23-H1, but also possibly resistance to UV-induced carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1445. doi:10.1158/1538-7445.AM2011-1445