On binding specificity of (6-4) photolyase to a T(6-4)T DNA photoproduct

Katrine Aalbæk Jepsen, Ilia A. Solov'yov
European Physical Journal D
Different factors lead to DNA damage and if it is not repaired in due time, the damaged DNAcould initiate mutagenesis and cancer. To avoid this deadly scenario, specific enzymes can scavenge and
repair the DNA, but the enzymes have to bind first to the damaged sites. We have investigated this binding
for a specific enzyme called (6-4) photolyase, which is capable of repairing certain UV-induced damage in
DNA. Through molecular dynamics simulations we describe the binding between the photolyase and the
DNA and reveal that several charged amino acid residues in the enzyme, such as arginines and lysines turn\øut to be important. Especially R421 is crucial, as it keeps the DNA strands at the damaged site inside
the repair pocket of the enzyme separated. DNA photolyase is structurally highly homologous to a protein
called cryptochrome. Both proteins are biologically activated similarly, namely through flavin co-factor
photoexcitation. It is, however, striking that cryptochrome cannot repair UV-damaged DNA. The present
investigation allowed us to conclude on the small but, apparently, critical differences between photolyase
and cryptochrome. The performed analysis gives insight into important factors that govern the binding of
UV-damaged DNA and reveal why cryptochrome cannot have this functionality.