title: YNK1, the yeast homolog of human metastasis suppressor NM23, is required for repair of UV radiation- and etoposide-induced DNA damage.
abstract: In humans, NM23-H1 is a metastasis suppressor whose expression is reduced in metastatic melanoma and breast carcinoma cells, and which possesses the ability to inhibit metastatic growth without significant impact on the transformed phenotype. NM23-H1 exhibits three enzymatic activities in vitro, each with potential to maintain genomic stability, a 3'-5' exonuclease and two kinases, nucleoside diphosphate kinase (NDPK), and protein histidine kinase. Herein we have investigated the potential contributions of NM23 proteins to DNA repair in the yeast, Saccharomyces cerevisiae, which contains a single NM23 homolog, YNK1. Ablation of YNK1 delayed repair of UV- and etoposide-induced nuclear DNA damage by 3-6h. However, YNK1 had no impact upon the kinetics of MMS-induced DNA repair. Furthermore, YNK1 was not required for repair of mitochondrial DNA damage. To determine whether the nuclear DNA repair deficit manifested as an increase in mutation frequency, the CAN1 forward assay was employed. An YNK1 deletion was associated with increased mutation rates following treatment with either UV (2.6x) or MMS (1.6 x). Mutation spectral analysis further revealed significantly increased rates of base substitution and frameshift mutations following UV treatment in the ynk1Delta strain. This study indicates a novel role for YNK1 in DNA repair in yeast, and suggests an anti-mutator function that may contribute to the metastasis suppressor function of NM23-H1 in humans.
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, KY 40536-0298, USA.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Yang
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Jarrett
authors.forename: Rolf
authors.initials: R
authors.lastname: Craven
authors.forename: David M
authors.initials: DM
authors.lastname: Kaetzel
mesh_terms: D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects*; D005047:Etoposide / Q000494:pharmacology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics*; D009701:Nucleoside-Diphosphate Kinase / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D024101:Mitochondrial Proteins; D054778:NM23 Nucleoside Diphosphate Kinases; D029701:Saccharomyces cerevisiae Proteins; D005047:Etoposide; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; C473137:YNK1 protein, S cerevisiae