DNA Damage Recognition and Nucleotide Excision Repair in Mammalian Cells

Excerpt

Frequently occurring DNA lesions are continuously removed from mammalian genomes by repair mechanismsthat excise and replace damaged bases and nucleotides. Amechanism called base excision repair (BER) worksmainly on common modifications caused by endogenousfactors such as water, oxygen, and heat. Nucleotide excision repair (NER) operates mainly on helix-distortingdamage caused by environmental mutagens. There aremany such mutagens. For human beings, the most important self-inflicted agent is tobacco smoke, which is responsible worldwide for more cancer deaths than anyother identified chemical source. Natural exposure tomore than fairly harmless doses of other environmentalmutagens is relatively rare in the West, with one exception. For humans and many organisms, the most important environmental agent is the ultraviolet (UV) component of sunlight. The main DNA lesions are dipyrimidinephotoproducts, principally cyclobutane pyrimidinedimers and (6-4) photoproducts. These lesions are cytotoxic and mutagenic. Mutations inactivating tumor suppressor genes in skin cancer, for example p53, often exhibit the signature pattern of UV-induced sequencechanges in two adjacent pyrimidine residues in DNA.The main function of the NER pathway is the removal ofUV-induced lesions from DNA, and defects in this pathway in human cells lead to the serious cancer-prone inherited disease xeroderma pigmentosum (XP). Remarkably, humans have no backup pathway for this importantdefense mechanism, and individuals without NER are totally unable to excise pyrimidine dimers from DNA. Thissituation seems unique to placental mammals, becauselower eukaryotes, plants, and bacteria all have additionaldefense systems against UV light, such as DNA photolyases to monomerize dimers, or DNA glycosylases ornucleases that specifically incise DNA at dipyrimidinephotoproducts. Early mammalian ancestors were small,furry, and nocturnal, so apparently there was little selection pressure to preserve a backup system to NER forhandling large amounts of UV damage. With modernchanges in human behavior involving frequent exposureby lightly pigmented individuals to intense solar radiation, it is unfortunate that human evolution did not retaineither an additional UV repair system or a cerebral cortexwith greater powers of judgement regarding exposure tomutagens.HUMAN PROTEINS FOR DUAL INCISION AN...