title: Metastasis suppressor NM23-H1 promotes repair of UV-induced DNA damage and suppresses UV-induced melanomagenesis.
abstract: Reduced expression of the metastasis suppressor NM23-H1 is associated with aggressive forms of multiple cancers. Here, we establish that 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, are novel participants in the cellular response to UV radiation (UVR)-induced DNA damage. NM23-H1 deficiency compromised the kinetics of repair for total DNA polymerase-blocking lesions and nucleotide excision repair of (6-4) photoproducts in vitro. Kinase activity of NM23-H1 was critical for rapid repair of both polychromatic UVB/UVA-induced (290-400 nm) and UVC-induced (254 nm) DNA damage, whereas its 3'-5' exonuclease activity was dominant in the suppression of UVR-induced mutagenesis. Consistent with its role in DNA repair, NM23-H1 rapidly translocated to sites of UVR-induced (6-4) photoproduct DNA damage in the nucleus. In addition, transgenic mice hemizygous-null for nm23-m1 and nm23-m2 exhibited UVR-induced melanoma and follicular infundibular cyst formation, and tumor-associated melanocytes displayed invasion into adjacent dermis, consistent with loss of invasion-suppressing activity of NM23 in vivo. Taken together, our data show a critical role for NM23 isoforms in limiting mutagenesis and suppressing UVR-induced melanomagenesis.
authors.affiliation: Department of Molecular and Biomedical Pharmacology, and Graduate Center for Toxicology, University of Kentucky College of Medicine and Markey Cancer Center, Lexington, Kentucky 40536, USA.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Jarrett
authors.forename: Marian
authors.initials: M
authors.lastname: Novak
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dabernat
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Daniel
authors.forename: Isabel
authors.initials: I
authors.lastname: Mellon
authors.forename: Qingbei
authors.initials: Q
authors.lastname: Zhang
authors.forename: Nathan
authors.initials: N
authors.lastname: Harris
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ciesielski
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenstermaker
authors.forename: Diane
authors.initials: D
authors.lastname: Kovacic
authors.forename: Andrzej
authors.initials: A
authors.lastname: Slominski
authors.forename: David M
authors.initials: DM
authors.lastname: Kaetzel
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008546:Melanoma, Experimental / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics / Q000502:physiology*; D009381:Neoplasms, Radiation-Induced / Q000517:prevention & control*; D014466:Ultraviolet Rays
chemical_list: D054778:NM23 Nucleoside Diphosphate Kinases; D007041:Hypoxanthine Phosphoribosyltransferase
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