A neomorphic cancer cell-specific role of MAGE-A4 in trans-lesion synthesis

• Published in: Nature communications Vol. 7; no. 1; pp. 12105 - 14
• Main Authors: Gao, Yanzhe, Mutter-Rottmayer, Elizabeth, Greenwalt, Alicia M., Goldfarb, Dennis, Yan, Feng, Yang, Yang, Martinez-Chacin, Raquel C., Pearce, Kenneth H., Tateishi, Satoshi, Major, Michael B., Vaziri, Cyrus
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.07.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337/1427; 631/337/474/2073; 631/80/86; A549 Cells; Animals; Antigens; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Biology; Cancer; Cell cycle; Cell Line; Cell Line, Tumor; Chemical synthesis; Cloning, Molecular; Curricula; Damage detection; Damage tolerance; Deoxyribonucleic acid; Depletion; DNA; DNA biosynthesis; DNA Damage; DNA polymerase; DNA Repair; DNA Replication; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-directed DNA polymerase; Ectopic expression; Escherichia coli - genetics; Escherichia coli - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; Fibroblasts - radiation effects; Gene Expression Regulation, Neoplastic; Genetic Vectors - chemistry; Genetic Vectors - metabolism; Genomes; Genotoxicity; HCT116 Cells; HeLa Cells; Histones - genetics; Histones - metabolism; Humanities and Social Sciences; Humans; Immunological tolerance; Irradiation; Lesions; Melanoma; Mice; multidisciplinary; Mutagenesis; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Protein biosynthesis; Radiation damage; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Replication; Science; Science (multidisciplinary); Signal Transduction; Skin cancer; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Ultraviolet radiation; Ultraviolet Rays; North Carolina; United States > US
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12105

Trans-lesion synthesis (TLS) is an important DNA-damage tolerance mechanism that permits ongoing DNA synthesis in cells harbouring damaged genomes. The E3 ubiquitin ligase RAD18 activates TLS by promoting recruitment of Y-family DNA polymerases to sites of DNA-damage-induced replication fork stalling. Here we identify the cancer/testes antigen melanoma antigen-A4 (MAGE-A4) as a tumour cell-specific RAD18-binding partner and an activator of TLS. MAGE-A4 depletion from MAGE-A4-expressing cancer cells destabilizes RAD18. Conversely, ectopic expression of MAGE-A4 (in cell lines lacking endogenous MAGE-A4) promotes RAD18 stability. DNA-damage-induced mono-ubiquitination of the RAD18 substrate PCNA is attenuated by MAGE-A4 silencing. MAGE-A4-depleted cells fail to resume DNA synthesis normally following ultraviolet irradiation and accumulate γH2AX, thereby recapitulating major hallmarks of TLS deficiency. Taken together, these results demonstrate a mechanism by which reprogramming of ubiquitin signalling in cancer cells can influence DNA damage tolerance and probably contribute to an altered genomic landscape. RAD18 is an important protein in trans-lesion synthesis, an error-prone damage-tolerant mode of DNA replication. Here the authors show that MAGE-A4 stabilizes RAD18 and allows cancer cells to maintain on-going DNA synthesis in the face of genotoxic injury.