Analysis of Meiotic Cancer Testis Antigens and Their Contribution to Tumorigenesis
Tumors frequently activate the expression of genes that are only otherwise required for meiosis. These Cancer Testes Antigens (CTAs) have been found to play critical roles in multiple cellular processes when aberrantly expressed in cancer. Here I found that the CTAs SPO11, GAGE and HORMAD1 play critical roles in cell survival, modulating response to DNA damaging agents, and DNA replication stress mitigation respectively. More specifically, we find HORMAD1 is critical for protecting stalled DNA replication forks in LUAD. Loss of HORMAD1 leads to nascent DNA degradation, an event which is mediated by the MRE11-DNA2-BLM pathway. Moreover, following exogenous induction of DNA replication stress, HORMAD1 deleted cells accumulate single stranded DNA (ssDNA). We find that these phenotypes are the result of a lack of RAD51 and BRCA2 loading onto stalled replication forks. Ultimately, loss of HORMAD1 leads to increased DNA breaks and chromosomal aberrations in response to replication stress. Collectively, our work supports the hypothesis that CTAs become abnormally expressed in cancer to buttress oncogenic behaviors and given their restrictive expression to the testes and tumors, they are unique targets with a broad therapeutic window.
DNA Replication, DNA-Binding Proteins, Genomic Instability, Neoplasms, Antigens, Neoplasm, DNA
University of Texas Southwestern Medical Center
Networked Digital Library of Theses and Dissertations