DNA Damage Recognition and Repair in Mammalian Global Genome Nucleotide Excision Repair

Abstract

The intrinsic instability of genomic DNA renders it susceptible to damage by spontaneously produced by-products such as reactive oxygen species and aldehyde metabolites or environmental genotoxins such as radiation and chemicals. Unrepaired DNA damage interferes with essential DNA transactions, such as replication and transcription, and eventually gives rise to the alteration of genetic information. Because genomic instability can cause cell death or carcinogenesis, DNA damage must be recognized and repaired as quickly as possible. Several mechanisms of DNA repair that function according to the type of damage underlie a highly sensitive system capable of detecting a few sites of damage among the large amount of normal DNA in the genome. Nucleotide excision repair (NER) is a major DNA repair pathway that can eliminate a wide spectrum of damage. In mammals, NER is executed by two subpathways: global genome repair (GGR) and transcription-coupled repair. Both subpathways share common core NER factors but possess unique systems for recognizing DNA damage. Transcription-coupled repair is initiated by the stalling of RNA polymerase II and is responsible for the accelerated repair of DNA damage in the transcribed strand of active genes. By contrast, GGR is initiated by xeroderma pigmentosum group C (XPC) and/or the UV-damaged DNA-binding protein (UV-DDB) complex, followed by the sequential actions of other NER-associated factors. This chapter reviews the molecular mechanisms underlying the recognition and repair of DNA damage by mammalian GGR.