Structure of DNA lesions may affect repair of DNA
NIEHS grantees and colleagues have discovered how proteins involved in the nucleotide excision repair (NER) DNA repair process identify DNA lesions, or structural damage, for removal. The findings provide evidence as to why some lesions triggered by environmental and other agents get repaired, while others remain and may lead to mutations and cancer.
DNA repair begins when the xeroderma pigmentosum C protein complex (XPC) patrols the genome for certain types of DNA lesions. Upon encountering damaged DNA, it inserts a simple protein structure shaped like a hairpin between the two DNA strands so NER proteins can recognize the lesion and remove it. In this study, the researchers described the molecular pathway that Rad4, a yeast version of XPC, takes when it binds to DNA lesions that occur from exposure to benzo[a]pyrene, a combustion byproduct in tobacco smoke and coal tar.
Using a supercomputer, researchers simulated the lesion recognition pathway at an atomic level and found that the structure of the DNA lesion can affect how it is recognized by XPC. For XPC to initially insert the hairpin-like structure, the lesion must contain an extruded and flipped cytosine, one of the four bases found in DNA. They also found that the repair process for benzo[a]pyrene lesions differed significantly from that of a ultraviolet light–induced lesion.
According to the authors, these findings may explain why some people are more vulnerable to DNA damage from certain chemicals and may inform the design of chemotherapeutic drugs that target DNA in cancer cells.
Citation: Mu H, Geacintov NE, Min JH1, Zhang Y, Broyde S. 2017. Nucleotide excision repair lesion-recognition protein Rad4 captures a pre-flipped partner base in a benzo[a]pyrene-derived DNA lesion: how structure impacts the binding pathway. Chem Res Toxicol 30(6):1344-1354.