The crucial role of DNA polymerase eta in protecting against sunlight-induced tumors is evidenced in Xeroderma Pigmentosum Variant (XP-V) patients, who carry mutations in this protein and present increased frequency of skin cancer.
Disrupting either the DNA annealing factor RAD52 or the A-family DNA polymerase POLQ can cause synthetic lethality with defects in BRCA1 and BRCA2, which are tumor suppressors important for homology-directed repair of DNA double-strand breaks (DSBs), and protection of stalled replication forks.
Interestingly we showed that the clinically approved proteasome inhibitor, Bortezomib restores the levels of Polη(721) suggesting that this might be a therapeutic approach to preventing tumor development in certain XP-V patients harboring missense mutations.
Nine of these candidate genes were selected for further qRT-PCR validation and 3 of them (ALDOA, AHSA1, and POLQ) were frequently found upregulated in OSCC samples, which may indicate an association of these genes with the carcinogenesis process in this tumor site and they can constitute potential new targets for therapy.
Subsequent investigations showed that POLQ knockdown resulted in radiosensitization of a panel of tumor cell lines from different primary sites while having little or no effect on normal tissue cell lines.
We found that a significant number of tumours overexpressed POLQ and that overexpression was correlated with ER negative disease (p=0.047) and high tumour grade (p=0.004), both of which are associated with poor clinical outcomes.
In conclusion, this screen of DNA repair genes implicates PRKDC and POLQ as candidate tumor suppressor genes involved in breast cancer and suggests that inactivating mutations in RAD50 predispose to pancreatic cancer as well as breast cancer.
The XPV gene encodes DNA polymerase eta, which catalyzes an accurate translesion synthesis, indicating that the XPV gene contributes tumor suppression in normal individuals.