Deciphering the Role of Cancer‐Testis Antigen (CTA) MAGEA9 in Regulating DNA Repair Pathway Proteins MSH2 and MSH6

Abstract

Cancer is a disease characterized by uncontrolled cell division and is one of the leading causes of death worldwide. In 2021, 1.8 million new cancer cases and 608,570 cancer‐related deaths are projected in the United States. Current cancer treatments are limiting, as they do not consider the differences in the epigenetic and genetic makeup of every patient, which explains why certain therapies may work for one patient but not another. Cancer‐specific proteins have garnered significant interest for precision medicine applications. Cancer testis antigens (CTAs) are a group of tumor antigens with gene expression restricted to the male germ cells in the testis. The Melanoma Antigen Gene (MAGE) protein family is one of the largest groups of CTAs. The MAGE protein family is highly conserved, and all share a common MAGE homology domain. Interestingly, while MAGEs are typically restricted to reproductive tissues, they are aberrantly expressed in cancer. MAGEs are categorized by expression pattern, as Type I MAGEs are strictly expressed in the testis while Type II MAGEs are ubiquitously expressed throughout the body. MAGEA9 belongs to the Type I family of MAGEs and expression correlates with poor patient outcome. Data from our lab indicates that expression of MAGEA9 results in increased cell proliferation and anchorage‐independent growth. Furthermore, we have identified MAGEA9 as a potential regulator of MSH2 and MSH6, two DNA repair pathway proteins that are involved in mismatch recognition and repair. Our goals are therefore to elucidate the molecular mechanism by which MAGEA9 affects MSH2 and MSH6 protein levels. To confirm interaction of MAGEA9 with MSH2 and MSH6 at the protein level, we will use co‐immunoprecipitation, co‐localization, and in vitro binding studies. In addition, we will perform CHX chase assays to determine the effect of MAGEA9 on MSH2 and MSH6 steady‐state levels. We will then use DNA repair assays to assess the overall effect of MAGEA9 on DNA mismatch repair. Collectively, these findings will provide a clearer understanding for the function of MAGEA9 in tumorigenesis, which may provide further insight for the development of novel therapeutic interventions.