title: The case for 8,5'-cyclopurine-2'-deoxynucleosides as endogenous DNA lesions that cause neurodegeneration in xeroderma pigmentosum.
abstract: Patients with the genetic disease xeroderma pigmentosum (XP) lack the capacity to carry out a specific type of DNA repair process called nucleotide excision repair (NER). The NER pathway plays a critical role in the repair of DNA damage resulting from ultraviolet (UV) radiation. A subset of XP patients develops a profound neurodegenerative condition known as XP neurological disease. Robbins and colleagues [Andrews A, Barrett S, Robbins J (1978) Xeroderma pigmentosum neurological abnormalities correlate with the colony forming ability after ultraviolet irradiation. Proc Natl Acad Sci U S A 75:1984-1988] hypothesized that since UV light cannot reach into the human brain, XP neurological disease results from some form of endogenous DNA damage that is normally repaired by the NER pathway. In the absence of NER, the damage accumulates, causing neuronal death by blocking transcription. In this manuscript, I consider the evidence that a particular class of oxidative DNA lesions, the 8,5'-cyclopurine-2'-deoxynucleosides, fulfills many of the criteria expected of neurodegenerative DNA lesions in XP. Specifically, these lesions are chemically stable, endogenous DNA lesions that are repaired by the NER pathway but not by any other known process, and strongly block transcription by RNA polymerase II in cells from XP patients. A similar set of criteria might be used to evaluate other candidate DNA lesions responsible for neurological diseases resulting from defects in other DNA repair mechanisms as well.
authors.affiliation: Section on Molecular Neurobiology, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane, Room 3S32, MSC 9412, Rockville, MD 20852, USA. pjbrooks@mail.nih.gov
authors.forename: P J
authors.initials: PJ
authors.lastname: Brooks
mesh_terms: D003057:Cockayne Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004249:DNA Damage / Q000235:genetics* / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D015394:Molecular Structure; D011684:Purine Nucleosides / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D014983:Xeroderma Pigmentosum / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D011684:Purine Nucleosides; D012319:RNA Polymerase II; D045643:DNA Repair Enzymes