TY - JOUR
T1 - A neomorphic cancer cell-specific role of MAGE-A4 in trans-lesion synthesis
AU - Gao, Yanzhe
AU - Mutter-Rottmayer, Elizabeth
AU - Greenwalt, Alicia M.
AU - Goldfarb, Dennis
AU - Yan, Feng
AU - Yang, Yang
AU - Martinez-Chacin, Raquel C.
AU - Pearce, Kenneth H.
AU - Tateishi, Satoshi
AU - Major, Michael B.
AU - Vaziri, Cyrus
N1 - Funding Information:
This study was supported by grant R01 ES09558 from the National Institutes of Health to C.V., F31 fellowship CA177179 from the National Institutes of Health to A.M.G. and by a Tier 1 Pilot Award from the University of North Carolina Lineberger Comprehensive Cancer Center to Y.G.
PY - 2016/7/5
Y1 - 2016/7/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84977571936&partnerID=8YFLogxK
U2 - 10.1038/ncomms12105
DO - 10.1038/ncomms12105
M3 - Article
C2 - 27377895
AN - SCOPUS:84977571936
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 12105
ER -