Thermodynamic Cooperativity and Kinetic Proofreading in DNA Damage Recognition and Repair

Abstract

In humans UV-induced cyclobutane thymine dimers are excised by the joint action of six repair factors, RPA, XPA, XPC, TFIIH, XPG, and XPF•ERCC1. Yet, in vitro assays show that none of these six factors is capable of detectably discriminating thymine dimer-containing DNA from undamaged DNA. We show how two elementary principles in macromolecular recognition, (1) cooperativity and (2) kinetic proofreading, are utilized to confer specificity to the repair system where none exists at the individual repair factor level and enable human cells to excise thymine dimers with a physiologically relevant specificity and at a biologically acceptable rate.