Characterizing the role of POLQ variants in genomic instability and cancer

Abstract

Melanoma is the most serious form of skin cancer that arises from melanocytes. It is developed due to ultra‐violet (UV) radiation inducing DNA damage when left unrepaired lead to mutations, which lead to genomic instability. Unrepaired DNA, or its faulty repair, can lead to mutagenesis, which can propagate further through rounds of replication, eventually resulting in uncontrolled cell growth leading to cancer. However, cells have various kinds of DNA repair pathways, which includes specialized enzymes that can repair DNA. One of the most important DNA repair enzyme is DNA polymerase theta (Pol θ or POLQ). POLQ has been shown to be involved in double strand break repair through a non‐canonical DNA end‐joining pathway known as the micro‐homology mediated end‐joining (MMEJ). POLQ is a low fidelity DNA polymerase and it introduces various kinds of mutations during DNA repair. Previous reports show that breast cancer patients that overexpress POLQ tend to have poorer survival rate indicating a potential role for POLQ in cancer. In collaboration with the Yale SPORE in Skin Cancer and Rhode Island College, we have identified several variants of POLQ in melanoma patients. Here we demonstrate that the variants of POLQ induce genomic instability and have accumulations of DNA double strand breaks (DSBs). We show that POLQ variants are sensitive to DNA damaging agents like etoposide. In addition, biochemical studies indicate that some of these variants display a slower polymerization rate compared to wild‐type (WT) suggesting a different mechanism for nucleotide incorporation. Together, this suggests that the cancer‐associated variants lead to genomic instability. Our studies suggest that variants of POLQ alter the DNA repair landscape and has potential to impact cancer treatment.Support or Funding InformationThis research was supported by Linfield College Start‐Up Funds and Linfield College Faculty Student Research Collaborative Grant (FSRCG) to SR.