Molecular mechanism of nucleotide excision repair

• Published in: Genes & development 1999-04, Vol.13 (7), p.768-785
• Main Authors: de Laat, W L, Jaspers, N G, Hoeijmakers, J H
• Format: Article
• Language: English
• Subjects: Chromatin - metabolism; DNA Repair; DNA-Binding Proteins - genetics; Endonucleases; Humans; Models, Genetic; Nuclear Proteins; Proteins - genetics; Replication Protein A; Transcription Factor TFIIH; Transcription Factors - genetics; Transcription Factors, TFII; Ultraviolet Rays - adverse effects; Xeroderma Pigmentosum - genetics; Xeroderma Pigmentosum Group A Protein
• ISSN: 0890-9369
• DOI: 10.1101/gad.13.7.768

From its very beginning, life has faced the fundamental problem that the form in which genetic information is stored is not chemically inert. DNA integrity is challenged by the damaging effect of numerous chemical and physical agents, compromizing its function. To protect this Achilles heel, an intricate network of DNA repair systems has evolved early in evolution. One of these is nucleotide excision repair (NER), a highly versatile and sophisticated DNA damage removal pathway that counteracts the deleterious effects of a multitude of DNA lesions, including major types of damage induced by environmental sources. The most relevant lesions subject to NER are cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs), two major kinds of injury produced by the shortwave UV component of sunlight. In addition, numerous bulky chemical adducts are eliminated by this process. Within the divergent spectrum of NER lesions, significant distortion of the DNA helix appears to be a common denominator. Defects in NER underlie the extreme photosensitivity and predisposition to skin cancer observed with the prototype repair syndrome xeroderma pigmentosum (XP). Seven XP complementation groups have been identified, representing distinct repair genes XPA-G (discussed in detail below). Two modes of NER can be distinguished: repair of lesions over the entire genome, referred to as global ge-nome NER (GG-NER), and repair of transcription-blocking lesions present in transcribed DNA strands, hence called transcription-coupled NER (TC-NER). Most XP groups harbor defects in a common component of both NER subpathways. GG-NER is dependent on the activity of all factors mentioned above, including the GG-NER-specific complex XPC-hHR23B. The rate of repair for GG-NER strongly depends on the type of lesion. For instance, 6-4PPs are removed much faster from the ge-nome than CPDs, probably because of differences in affinity of the damage sensor XPC-hHR23B. In addition, the location (accessibility) of a lesion influences the removal rate in vivo. In TC-NER, damage is detected by the elongating RNA polymerase II complex when it encounters a lesion. Interestingly, a distinct disorder, Cockayne syndrome (CS), is associated with a specific defect in transcription-coupled repair. The identification of two complementation groups (CS-A and CS-B) shows that at least two gene products are specifically needed for fast and efficient repair of transcribed strands. Phenotypically, CS is a very