In vitro repair of oxidative DNA damage by human nucleotide excision repair system: Possible explanation for neurodegeneration in Xeroderma pigmentosum patients

In vitro repair of oxidative DNA damage by human nucleotide excision repair system: Possible explanation for neurodegeneration in Xeroderma pigmentosum patients

^*Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599; and ^†Department of Chemistry, Wesleyan University, Middletown, CT 06459

Edited by Charles M. Radding, Yale University School of Medicine, New Haven, CT, and approved June 11, 1997 (received for review March 27, 1997)

Abstract

Xeroderma pigmentosum (XP) patients fail to remove pyrimidine dimers caused by sunlight and, as a consequence, develop multiple cancers in areas exposed to light. The second most common sign, present in 20–30% of XP patients, is a set of neurological abnormalities caused by neuronal death in the central and peripheral nervous systems. Neural tissue is shielded from sunlight-induced DNA damage, so the cause of neurodegeneration in XP patients remains unexplained. In this study, we show that two major oxidative DNA lesions, 8-oxoguanine and thymine glycol, are excised from DNA in vitro by the same enzyme system responsible for removing pyrimidine dimers and other bulky DNA adducts. Our results suggest that XP neurological disease may be caused by defective repair of lesions that are produced in nerve cells by reactive oxygen species generated as by-products of an active oxidative metabolism.

Footnotes

↵ ‡ To whom reprint requests should be addressed.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: XP, xeroderma pigmentosum; 8-OxoG, 8-oxoguanine; Tg, thymine glycol; T<>T, cis, syn-cyclobutane thymine dimer; CHO, Chinese hamster ovary; CFE, cell-free extract; CS, Cockayne’s Syndrome; AP, abasic; TCR, transcription-coupled repair; CG, complementation group.