RETRACTED: Transcription-Coupled Repair of 8-oxoGuanine

Abstract

Analysis of transcription-coupled repair (TCR) of oxidative lesions here reveals strand-specific removal of 8-oxo-guanine (8-oxoG) and thymine glycol both in normal human cells and xeroderma pigmentosum (XP) cells defective in nucleotide excision repair. In contrast, Cockayne syndrome (CS) cells including CS-B, XP-B/CS, XP-D/CS, and XP-G/CS not only lack TCR but cannot remove 8-oxoG in a transcribed sequence, despite its proficient repair when not transcribed. The XP-G/CS defect uniquely slows lesion removal in nontranscribed sequences. Defective TCR leads to a mutation frequency at 8-oxoG of 30%-40% compared to the normal 1%-4%. Surprisingly, unrepaired 8-oxoG blocks transcription by RNA polymerase II. These data imply that TCR is required for polymerase release to allow repair and that CS results from defects in TCR of oxidative lesions.

Mitochondrial repair of 8-oxoguanine is deficient in Cockayne syndrome group B

“…Cells from CS patients are more sensitive than wild type cells to DNA damage induced by ultraviolet (UV) light (Wade and Chu, 1979), 4-Nitroquinoline-1-oxide (4NQO) (Wade and Chu, 1979), N-acetoxy-2-acetylaminofluorene (NA-AAF) (van Oosterwijk et al, 1996), ionizing radiation, and hydrogen peroxide (Cooper et al, 1997;Leadon and Cooper, 1993). CS cells are deficient in transcription coupled repair (TCR) of lesions caused by UV irradiation (Evans and Bohr, 1994;Venema et al, 1990) or oxidative stress (Cooper et al, 1997;Le Page et al, 2000). Furthermore, RNA synthesis recovers more slowly in UV-treated CS cells than in wild type cells .…”

Base excision repair of adenine/8-oxoguanine mispairs by an aphidicolin-sensitive DNA polymerase in human cell extracts

“…Mismatch repair proteins may also help in the control of DNA oxidation levels (Leadon and Avrutskaya, 1997;DeWeese et al, 1998;Colussi et al, 2002). Transcription-coupled excision repair of 8oxoG guarantees the removal of the oxidized guanines from the transcribed strand of active genes (Le Page et al, 2000).…”

Global genome repair of 8-oxoG in hamster cells requires a functional CSB gene product

“…It has been shown that CS cells are de®cient in the nucleotide excision repair (NER) pathway that removes ultraviolet light (UV) induced lesions from the transcribed strand of active genes (van Ho en et al, 1993;Venema et al, 1990). Defective transcription-coupled repair (TCR) in CS cells is not only observed after UV irradiation, but also after oxidative stress Le Page et al, 2000b). The clinical features of CS are di cult to reconcile with a repair de®ciency limited to TCR of UV-induced or bulky lesions.…”

“…The clinical features of CS are di cult to reconcile with a repair de®ciency limited to TCR of UV-induced or bulky lesions. Consequently, it has been speculated that subtle defects in the repair of oxidative DNA lesions may contribute to the complex phenotype of a icted individuals Dianov et al, 1997Dianov et al, , 1999Le Page et al, 2000b;Nouspikel et al, 1997).…”

“…Using an in vitro approach with whole cell extracts (WCE) and oligonucleotide-based duplex substrates containing sitespeci®c lesions, we demonstrated earlier that human CS-B cells have a reduced capacity to make incisions at the base lesion 8-oxoG compared to extracts from normal cells . In a plasmid-based shuttle vector system, it has also been shown that CS cells exhibit reduced repair of 8-oxoG, which leads to a higher mutation frequency (Le Page et al, 2000b).…”