Genome instability increases the risk for cancer. Among the diverse types of DNA damage, DNA double stranded breaks (DSBs) can drive genomic instability by their potential to induce genome rearrangements. Homologous recombination (HR) functions to accurately repair DSBs and help maintain genomic integrity. BRCA2 is a central HR protein and recruits other proteins such as RAD51 in somatic cells and RAD51 and DMC1 in germline cells to participate in the two signature steps of HR: 1) Homology search and 2) DNA strand invasion. Loss of BRCA2 and RAD51 function is associated with increased risk of breast, ovarian and other cancers.
SYCP3 is an essential structural component of the meiosis-specific synaptonemal complex and is typically expressed only in germline cells (e.g., in testis, ovary) but not in somatic cells. Emerging evidence indicates that SYCP3 is mis-expressed in certain cancer cells and primary tumors, and hence SYCP3 has been termed a cancer/testis antigen (CTA). SYCP3 mis-expression in somatic cells has been shown to cause a DNA repair defect. Recently, it was reported that SYCP3 interacts with BRCA2 and RAD51 and impairs their function in HR involving mechanisms that remain to be defined.
In this work, we perform a review of CTAs including SYCP3 that function in meiotic chromosome metabolism and have been suggested to be involved in carcinogenesis. We analyze cancer databases with tumor and cancer cell line data to understand CTA expression patterns and gain insight into mechanisms by which they lead to tumor formation.
SYCP3 mis-expression leads to functional BRCA2 deficiency which is a key factor associated with many breast cancers. The published studies that evaluate SCYP3 mis-expression in cancers are based on RNA transcript analysis which may not be indicative of SYCP3 protein levels. Our study is the first to analyze SYCP3 protein expression in breast cancers using immunohistochemistry (IHC) and our results show that about 33 % of breast cancers have SYCP3 misexpression.
In the final chapter, we establish a biochemical mechanism by which SYCP3 leads to functional loss of HR in somatic cells by in vitro assays using purified proteins. Our findings show that SYCP3 inhibits RAD51 activity in HR by binding to free RAD51 and disrupting RAD51 filament formation. Another critical recombination protein RAD54 overcomes the SYCP3-mediated inhibition of RAD51 function likely by competing with SYCP3 in the interaction with RAD51.
The findings from this project help determine the mechanism by which SYCP3 mis-expression in somatic cells leads to HR deficiency and establish SYCP3 expression in tumors as a potential biomarker for HR deficiency, which may also qualify patients for cancer therapeutics like Poly (ADP-ribose) polymerase inhibitors.
