Breaking and sealing one strand of DNA: the consequence of the Imbalance.
Breaks in one strand of DNA arise spontaneously every day from various sources including abortive activities of endogenous enzymes and reactive oxygen species produced during normal metabolic activities. These types of DNA breaks underlie the clinical utility of important classes of anti-cancer drugs and their progressive accumulation causes neurodegenration in humans. This is highlighted by defects in the 3’-DNA processing enzyme tyrosyl DNA phosphodiesterase (TDP1) which removes stalled topoisomerase 1 peptide from DNA termini. Despite this important catalytic function fulfilled by TDP1, it remains together with the newly identified enzyme TDP2 the only human enzymes that display this catalytic activity. Here, we employ a combination of yeast genetics, molecular, cellular, and whole animal approaches to understand the mechanisms of repair of this type of DNA break and determine their impact on neuronal viability and human health.