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

Yanzhe Gao, Elizabeth Mutter-Rottmayer, Alicia M. Greenwalt, Dennis Goldfarb, Feng Yan, Yang Yang, Raquel C. Martinez-Chacin, Kenneth H. Pearce, Satoshi Tateishi, Michael B. Major and Cyrus Vaziri ()
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Yanzhe Gao: University of North Carolina at Chapel Hill
Elizabeth Mutter-Rottmayer: University of North Carolina at Chapel Hill
Alicia M. Greenwalt: University of North Carolina at Chapel Hill
Dennis Goldfarb: University of North Carolina at Chapel Hill
Feng Yan: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Yang Yang: University of North Carolina at Chapel Hill
Raquel C. Martinez-Chacin: University of North Carolina at Chapel Hill
Kenneth H. Pearce: Center For Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
Satoshi Tateishi: Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University
Michael B. Major: University of North Carolina at Chapel Hill
Cyrus Vaziri: University of North Carolina at Chapel Hill

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12105

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