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Cancer‐associated variants of POLQ induce genomic instability
Author(s) -
Headrick Ashley,
Wanchu Sahaj,
Avalos Lisbeth,
Victorino Jorge,
TowleWeicksel Jamie,
Ray Sreerupa
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.457.7
Subject(s) - genome instability , dna repair , dna damage , dna polymerase , biology , cancer , polymerase , cancer research , nucleotide excision repair , mutagenesis , cancer cell , dna , genetics , mutation , gene
Melanoma is the most severe form of skin cancer and it develops when unrepaired DNA damage in skin cells causes mutations which further leads to genomic instability. The widely accepted environmental cause of melanoma is ultra‐violet (UV) radiation, which leads to DNA damage in skin cells. Failure to repair DNA, or its error‐prone repair, can lead to mutagenesis which can propagate further through rounds of replication, eventually resulting in uncontrolled cell growth leading to cancer. However, the cell has a mechanism for repair using a variety of highly specialized enzymes known as DNA polymerases. DNA Polymerase theta (Pol θ or POLQ) is hypothesized to be an important DNA polymerase involved in double‐strand break (DSB) repair through microhomology‐mediated end‐joining (MMEJ), an alternative non‐homologous end‐joining (alt‐NHEJ) pathway, however it is a low fidelity enzyme that often leads to numerous errors during repair. There is evidence that breast cancer patients that overexpress POLQ tend to have poorer survival rate suggesting 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 cancer‐associated variants of POLQ induce genomic instability and have accumulation of DNA DSBs. In addition, biochemical studies indicate that these variants display an inherently 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 and may play a role in cancer. Our studies suggest that variants of POLQ alter the DNA repair and has potential to impact the treatment of cancer. Support or Funding Information This research was supported by Linfield College Start‐Up Funds and Linfield College Faculty Student Research Collaborative Grant (FSRCG) to SR. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .