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

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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.

Abstract

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.

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Most cited references 42

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Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function.

Satya Prakash, Robert Johnson, Louise Prakash (2005)

This review focuses on eukaryotic translesion synthesis (TLS) DNA polymerases, and the emphasis is on Saccharomyces cerevisiae and human Y-family polymerases (Pols) eta, iota, kappa, and Rev1, as well as on Polzeta, which is a member of the B-family polymerases. The fidelity, mismatch extension ability, and lesion bypass efficiencies of these different polymerases are examined and evaluated in the context of their structures. One major conclusion is that, despite the overall similarity of basic structural features among the Y-family polymerases, there is a high degree of specificity in their lesion bypass properties. Some are able to bypass a particular DNA lesion, whereas others are efficient at only the insertion step or the extension step of lesion bypass. This functional divergence is related to the differences in their structures. Polzeta is a highly specialized polymerase specifically adapted for extending primer termini opposite from a diverse array of DNA lesions, and depending upon the DNA lesion, it contributes to lesion bypass in a mutagenic or in an error-free manner. Proliferating cell nuclear antigen (PCNA) provides the central scaffold to which TLS polymerases bind for access to the replication ensemble stalled at a lesion site, and Rad6-Rad18-dependent protein ubiquitination is important for polymerase exchange.

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The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta.

C Masutani, R Kusumoto, A. Yamada … (1999)

Xeroderma pigmentosum variant (XP-V) is an inherited disorder which is associated with increased incidence of sunlight-induced skin cancers. Unlike other xeroderma pigmentosum cells (belonging to groups XP-A to XP-G), XP-V cells carry out normal nucleotide-excision repair processes but are defective in their replication of ultraviolet-damaged DNA. It has been suspected for some time that the XPV gene encodes a protein that is involved in trans-lesion DNA synthesis, but the gene product has never been isolated. Using an improved cell-free assay for trans-lesion DNA synthesis, we have recently isolated a DNA polymerase from HeLa cells that continues replication on damaged DNA by bypassing ultraviolet-induced thymine dimers in XP-V cell extracts. Here we show that this polymerase is a human homologue of the yeast Rad30 protein, recently identified as DNA polymerase eta. This polymerase and yeast Rad30 are members of a family of damage-bypass replication proteins which comprises the Escherichia coli proteins UmuC and DinB and the yeast Rev1 protein. We found that all XP-V cells examined carry mutations in their DNA polymerase eta gene. Recombinant human DNA polymerase eta corrects the inability of XP-V cell extracts to carry out DNA replication by bypassing thymine dimers on damaged DNA. Together, these results indicate that DNA polymerase eta could be the XPV gene product.

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Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage.

Patricia L. Kannouche, Jonathan Wing, Alan Lehmann (2004)

Most types of DNA damage block replication fork progression during DNA synthesis because replicative DNA polymerases are unable to accommodate altered DNA bases in their active sites. To overcome this block, eukaryotic cells employ specialized translesion synthesis (TLS) polymerases, which can insert nucleotides opposite damaged bases. In particular, TLS by DNA polymerase eta (poleta) is the major pathway for bypassing UV photoproducts. How the cell switches from replicative to TLS polymerase at the site of blocked forks is unknown. We show that, in human cells, PCNA becomes monoubiquitinated following UV irradiation of the cells and that this is dependent on the hRad18 protein. Monoubiquitinated PCNA but not unmodified PCNA specifically interacts with poleta, and we have identified two motifs in poleta that are involved in this interaction. Our findings provide an attractive mechanism by which monoubiquitination of PCNA might mediate the polymerase switch.

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Author and article information

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 05 July 2016

Publication date Collection: 2016

Volume: 7

Electronic Location Identifier: 12105

Affiliations

[1 ]Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill , 101 Manning Drive, 614 Brinkhous-Bullitt Building, Chapel Hill, North Carolina 27599, USA

[2 ]Curriculum in Toxicology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, USA

[3 ]Curriculum in Genetics and Molecular Biology, University of North Carolina , Chapel Hill, North Carolina 27599, USA

[4 ]Department of Computer Science, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, USA

[5 ]Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, USA

[6 ]Department of Pharmacology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, USA

[7 ]Center For Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, USA

[8 ]Division of Cell Maintenance, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University , Honjo 2-2-1, Kumamoto 860-0811, Japan

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[a ] cyrus_vaziri@ 123456med.unc.edu

[*]

These authors contributed equally to this work

Article

Publisher Item ID: ncomms12105

DOI: 10.1038/ncomms12105

PMC ID: 4935975

PubMed ID: 27377895

SO-VID: 28f042e0-2a43-4414-9fb4-2b7ffdeb575f

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

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Most cited references 42

Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function.

The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta.

Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage.

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