Disorderly Conduct: Investigating Unstructured Sequence Inserts of Human DNA Polymerase Theta
Drogalis Beckham, Lea K
Drogalis Beckham, Lea K
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Abstract
After treatment with ionizing radiation, cancer cells must evade death by repairing the damage. This can involve DNA polymerase theta (pol theta), an error-prone DNA double-strand break (DSB) repair protein which functions through an alternative end-joining pathway termed theta-mediated end joining (TMEJ). TMEJ is a last resort pathway for DSB repair when the preferred homologous recombination (HR) and non-homologous end joining pathways are impaired. Upregulation of pol theta in breast cancer, non-small cell lung cancer, and oral squamous cell carcinoma is correlated with poor patient survival. In cancer cells with defective HR, inhibition of pol theta could be a useful adjuvant to ionizing radiation and other DNA-damaging cancer treatments. To achieve this goal, it is important to first identify the unique structural elements of pol theta that enable its specialized function. The C-terminal DNA synthesis domain harbors five disordered regions, not seen in lower eukaryotes, which affect both the overall structure and polymerase activity. Here, we use a powerful combination of biochemistry, X-ray crystallography, fluorescence-based DNA synthesis assays, dynamic light scattering, and size exclusion chromatography to study the structure and activity of pol theta mutants informed by the structure, as well as cancer variants.
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Graduate
Date
2021-01-01