Browsing by Subject "DNA polymerase beta"

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Aberrant DNA polymerase beta promotes genomic instability associated with gastric carcinogenesis and innate immunity
(2022-07-06) Zhao, Shengyuan; Kidane, Dawit; DiGiovanni, John; Vasquez, Karen; Tiziani, Stefano
Base excision repair (BER) is critical to maintain cellular genomic stability. Several BER genes, including DNA polymerase beta (Pol β), play an important role in tumor development as they facilitate the accurate repair of many lesions that arise from exogenous and endogenous DNA damaging agents. Mutation in DNA Pol β impacts BER efficiency and has been reported in approximately 30–40% of gastric carcinoma tumors. Here, we found that dRP lyase deficient variant of Pol β promotes genomic instability towards oxidative and alkylating DNA damaging agents in cell models. In addition, certain vulnerable regions of the genome, including telomere, is susceptible to the promoted DNA damage, and the resulting telomere instability can contribute to cancer development. Further, we applied transgenic mouse models carrying Pol β mutation and found increased level of DNA damage and proliferation in gastric tissues. Mice carrying Pol β mutation also exhibits higher level of immune cell infiltration and overexpression of pro-inflammatory chemokines and cytokines in gastric tissues. Pathological analysis indicates Pol β mutation promotes early-stage gastric cancer development. Our findings unveiled the significant role of Pol β in genomic stability, gastric cancer development, and its potential as a biomarker for gastric cancer diagnosis and treatment.
Structural analysis of hypoxanthine mutagenicity using DNA polymerase β and η
(2019-01-31) Hawkins, Michael Andrew; Lee, Seongmin
Cellular life is precarious. Dangers abound for a cell’s DNA, from both external and internal factors, and maintaining genomic integrity is crucial for cell survival. Oxidative damage, from reactive oxygen/nitrogen species, can cause deamination of adenine, producing hypoxanthine. Hypoxanthine (Hx) is the nucleobase in inosine and plays a role in the genetic disorder Lesch-Nyhan Syndrome. Crucially, hypoxanthine has the potential to be mutagenic due to its ability to pair with cytosine. Hypoxanthine can also pair with thymine, but we propose that Hx preferentially interacts with cytosine which can lead to a potential transition mutation (dA to dG). Our structural data indicates that cytosine is indeed the preferred bonding partner for Hx. The crystal structures of DNA polymerase beta and eta complexed with DNA containing Hx and incoming nonhydrolyzable dCTP and dTTP shows how the dCTP is in a better position for the nucleotidyl transfer reaction. This study provides a better understanding of the detailed molecular interactions underlying this potentially mutagenic DNA lesion.