A buildup of reactive oxygen species (ROS), a byproduct of many cellular processes, is associated with diseases including cancer. While ROS plays an important role in processes such as cell signaling and immune system function, at high levels it can also cause oxidative DNA damage, which is known to contribute to cancer initiation and progression.
One type of ROS associated DNA damage is the oxidation of guanine and formation of a lesion called an 8-oxoG adduct. Unrepaired 8-oxoG lesions are thought to contribute to somatic mutations in cancer. While the ability of 8-oxoG to cause mutations is well studied, how cellular factors like DNA repair processes and DNA-binding proteins impact the specific location where 8-oxoG mutations form is unknown.
Now, new work by Steven Roberts PhD, and graduate student Cameron Cordero along with collaborators from the University of Kansas and Vanderbilt University published in Nature Communications, finds oxidants, like ROS, can cause mutations through multiple mechanisms. These mechanisms including substitution mutations that involve changing a single DNA base and insertion/deletion mutations, where bases are added or deleted from the genome. The group also finds there is a wide range of over-lapping repair processes that cells use to limit 8-oxoG mutations. The authors correlated Cryo-EM structures and mutation patterns in whole genome sequencing data to show how topological factors in the genome can limit repair protein accessibility leading to enhanced 8-oxoG mutagenesis in more condensed chromatin states and nucleosomal DNA. This work highlights how combining state-of-the-art technologies like Cryo-EM and mutation signature analysis can increase our understanding of how mutations drive diseases such as cancer.
Future work from this study will focus on identifying the specific process responsible for 8-oxoG production in human cancers and determining if these mutations can be exploited for immune therapies.
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