PARP1 Incises Abasic Sites and Covalently Cross-links to 3′-DNA Termini via Cysteine Addition Not Reductive Amination
Xiaoying Wei, Kun Yang
Abstract
Poly [ADP-ribose] polymerase 1 (PARP1) is a ubiquitous nuclear enzyme that plays multifaceted roles in the cellular response to DNA damage. Previous studies demonstrated that PARP1 incises the most frequently formed DNA lesion, the apurinic/apyrimidinic (AP) site, and in the process is trapped as a DNA-PARP1 cross-link at the 3'-terminus. The covalent linkage was proposed to be composed of a secondary amine resulting from formal reductive amination of an initially formed incision product. PARP1 cysteine residues were proposed to reduce the initially formed Schiff base. Here, we report evidence to support a different mechanism in which DNA-PARP1 cross-links result from cysteine addition to incised AP sites.
Topics & Concepts
AP siteChemistryPARP1DNADNA damageCysteineCovalent bondDNA polymeraseBiochemistryReductive aminationBase excision repairPolymerasePoly ADP ribose polymeraseBiophysicsEnzymeBiologyOrganic chemistryCatalysisPARP inhibition in cancer therapyDNA Repair MechanismsCRISPR and Genetic Engineering