Mutations of the ING1 tumor suppressor gene detected in human melanoma abrogate nucleotide excision repair.
Epidemiological evidence indicates that ultraviolet radiation (UVR) is the primary environmental cause of the rapid increase in the incidence of human cutaneous melanoma observed in the past decades. However, the genetic changes caused by UVR that lead to melanoma formation remain unclear. The ING1 (inhibitor of growth 1) tumor suppressor plays an important role in cellular stress response to UVR. To further investigate whether ING1 is involved in melanoma development, we examined the mutational status of the ING1 gene in 46 human cutaneous melanoma biopsies and characterized the biological importance of ING1 mutations in nucleotide excision repair. Single-strand conformation polymorphism and DNA sequencing were used to detect the mutational status of the ING1 gene. The host-cell-reactivation assay and radioimmunoassay were used to determine the role of ING1 mutations in nucleotide excision repair. We show that 20% of the melanoma primaries contained missense mutations in the SAP30-interacting domain and PHD finger motif of the ING1 gene with the R102L and N260S alterations observed more than once. Furthermore, our data indicate that patients that harbor ING1 mutations in the tumors have a higher risk to die from the disease within 5 years (50%) compared to patients with no ING1 mutation (18%). Moreover, we demonstrated that mutations at codon 102 or 260 as well as deletion of the PHD finger motif are detrimental to p33ING1-mediated enhancement of DNA repair. Taken together, our data indicate that ING1 mutations abrogate its enhancement in nucleotide excision repair.
Campos
Eric I
EI
Department of Medicine, Division of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada.
Martinka
Magdalena
M
Mitchell
David L
DL
Dai
Derek L
DL
Li
Gang
G
D019943:Amino Acid Substitution; D001483:Base Sequence; D018797:Cell Cycle Proteins; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009687:Nuclear Proteins; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D014162:Transfection; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins