Melanoma antigen-D2 controls cell cycle progression and modulates the DNA damage response

Trussart, Charlotte; Pirlot, Céline; Valentin, Emmanuel Di; Piette, Jacques; Habraken, Yvette

doi:10.1016/j.bcp.2018.01.035

Cited by 9 publications

(4 citation statements)

References 55 publications

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“…Based on our identification of a role for MAGE-A4 in genome maintenance, we hypothesized that additional CT antigens might help sustain cancer cells by promoting DNA repair. Potentially consistent with our hypothesis, several other studies have suggested effects of CT antigens on genome stability 7 , 20 , 21 . Accordingly we took a candidate gene approach to investigate possible connections between CT antigens and DNA repair.…”

Section: Introductionsupporting

confidence: 93%

The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells

Gao

Kardos

Yang

et al. 2018

Sci Rep

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The Cancer/Testes (CT) Antigen HORMAD1 is germ cell-restricted and plays developmental roles in generation and processing of meiotic DNA Double Strand Breaks (DSB). Many tumors aberrantly overexpress HORMAD1 yet the potential impact of this CT antigen on cancer biology is unclear. We tested a potential role of HORMAD1 in genome maintenance in lung adenocarcinoma cells. We show that HORMAD1 re-distributes to nuclear foci and co-localizes with the DSB marker γH2AX in response to ionizing radiation (IR) and chemotherapeutic agents. The HORMA domain and C-term disordered oligomerization motif are necessary for localization of HORMAD1 to IR-induced foci (IRIF). HORMAD1-depleted cells are sensitive to IR and camptothecin. In reporter assays, Homologous Recombination (HR)-mediated repair of targeted ISce1-induced DSBs is attenuated in HORMAD1-depleted cells. In Non-Homologous End Joining (NHEJ) reporter assays, HORMAD1-depletion does not affect repair of ISce1-induced DSB. Early DSB signaling events (including ATM phosphorylation and formation of γH2AX, 53BP1 and NBS1 foci) are intact in HORMAD1-depleted cells. However, generation of RPA-ssDNA foci and redistribution of RAD51 to DSB are compromised in HORMAD1-depleted cells, suggesting that HORMAD1 promotes DSB resection. HORMAD1-mediated HR is a neomorphic activity that is independent of its meiotic partners (including HORMAD2 and CCDC36. Bioinformatic analysis of TCGA data show that similar to known HR pathway genes HORMAD1 is overexpressed in lung adenocarcinomas. Overexpression of HR genes is associated with specific mutational profiles (including copy number variation). Taken together, we identify HORMAD1-dependent DSB repair as a new mechanism of radioresistance and a probable determinant of mutability in lung adenocarcinoma.

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Section: Introductionsupporting

confidence: 93%

The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells

Gao

Kardos

Yang

et al. 2018

Sci Rep

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“…The aberrant expression of meiotic genes in cancer cells has been shown to contribute to various hallmarks of cancer by altering centromeric polarity control, motility, chromosome dynamics and DNA repair (Hanahan and Weinberg, 2011;McFarlane and Wakeman, 2017) (Figure 1). In particular, alterations of how cancer cells repair DNA breaks due to unscheduled expression of meiotic genes, has been shown to drive genomic instability and to affect tumor cells' response to anticancer therapies (Nielsen and Gjerstorff, 2016;Mantere et al, 2017;Trussart et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Meiotic Genes and DNA Double Strand Break Repair in Cancer

2022

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Tumor cells show widespread genetic alterations that change the expression of genes driving tumor progression, including genes that maintain genomic integrity. In recent years, it has become clear that tumors frequently reactivate genes whose expression is typically restricted to germ cells. As germ cells have specialized pathways to facilitate the exchange of genetic information between homologous chromosomes, their aberrant regulation influences how cancer cells repair DNA double strand breaks (DSB). This drives genomic instability and affects the response of tumor cells to anticancer therapies. Since meiotic genes are usually transcriptionally repressed in somatic cells of healthy tissues, targeting aberrantly expressed meiotic genes may provide a unique opportunity to specifically kill cancer cells whilst sparing the non-transformed somatic cells. In this review, we highlight meiotic genes that have been reported to affect DSB repair in cancers derived from somatic cells. A better understanding of their mechanistic role in the context of homology-directed DNA repair in somatic cancers may provide useful insights to find novel vulnerabilities that can be targeted.

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“…The tumor suppressor protein, p53, regulates CDKN1A expression, and CDKN1A can induce p53-dependent cell cycle arrest at G1 in response to a variety of stressors [ 32 ]. Trussart et al discovered that melanoma antigen D2 regulates cell cycle progression and the DNA damage response in a variety of cancers [ 33 ]. According to Papageorgio et al, MAGED2 is a possible negative regulator of p53 activity, which could have consequences for cancer management and prognosis [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Expression and Prognostic Value of Melanoma-Associated Antigen D2 in Gliomas

Yan

Lenahan³

et al. 2022

Brain Sciences

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Introduction: The melanoma-associated antigen D2 (MAGED2) is one of the melanoma-associated antigen family members. It is commonly overexpressed in a variety of malignancies. However, the mechanism and function of MAGED2 in glioma remain unknown. Methods: The MAGED2 expression level and the correlations between clinical characteristics were analyzed with the data from the CGGA and TCGA datasets. MAGED2 expression in 98 glioma tissues was measured using RT-qPCR, Western blot, and immunohistochemistry. CCK-8, colony formation, and EdU assays were used to assess the effect of MAGED2 on U251-MG cell proliferation. Flow cytometry was used to track changes in the cell cycle and cell apoptosis following plasmid transfection with CRISPRi. Results: MAGED2 was shown to be highly expressed in glioma tissues, and high MAGED2 expression predicted poor prognosis. Furthermore, MAGED2 knockdown significantly inhibited the proliferation of U251-MG cells by preventing cell cycle arrest at the G0/G1 phase and triggering apoptosis. In line with in vitro findings, the results of the xenograft experiment and immunohistochemistry also showed that MAGED2 suppression inhibited tumor development and decreased Ki-67 expression levels. Conclusions: MAGED2 may be a possible biomarker for glioma and an important prognostic factor for glioma patients.

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Melanoma antigen-D2 controls cell cycle progression and modulates the DNA damage response

Cited by 9 publications

References 55 publications

The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells

The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells

Meiotic Genes and DNA Double Strand Break Repair in Cancer

Expression and Prognostic Value of Melanoma-Associated Antigen D2 in Gliomas

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