Preferential repair of ionizing radiation-induced damage in the transcribed strand of an active human gene is defective in Cockayne syndrome.

Abstract

Cells from patients with Cockayne syndrome (CS), which are sensitive to killing by UV although overall damage removal appears normal, are specifically defective in repair of UV damage in actively transcribed genes. Because several CS strains display cross-sensitivity to killing by ionizing radiation, we examined whether ionizing radiation-induced damage in active genes is preferentially repaired by normal cells and whether the radiosensitivity of CS cells can be explained by a defect in this process. We found that ionizing radiation-induced damage was repaired more rapidly in the transcriptionally active metallothionein IIA (MTIIA) gene than in the inactive MTIIB gene or in the genome overall in normal cells as a result of faster repair on the transcribed strand of MTIIA. Cells of the radiosensitive CS strain CS1AN are completely defective in this strand-selective repair of ionizing radiation-induced damage, although their overall repair rate appears normal. CS3BE cells, which are intermediate in radiosensitivity, do exhibit more rapid repair of the transcribed strand but at a reduced rate compared to normal cells. Xeroderma pigmentosum complementation group A cells, which are hypersensitive to UV light because of a defect in the nucleotide excision repair pathway but do not show increased sensitivity to ionizing radiation, preferentially repair ionizing radiation-induced damage on the transcribed strand of MTIIA. Thus, the ability to rapidly repair ionizing radiation-induced damage in actively transcribing genes correlates with cell survival. Our results extend the generality of preferential repair in active genes to include damage other than bulky lesions.

The Yeast TFB1 and SSL1 Genes, Which Encode Subunits of Transcription Factor IIH, Are Required for Nucleotide Excision Repair and RNA Polymerase II Transcription

“…Other DNA repair processes (such as BER) may not be limited by this accessibility problem and hence are not directly coupled to transcription. This hypothesis, which seeks to explain the coupling of the transcription and DNA repair processes, does not necessarily contradict reports in the literature which suggest that forms of base damage which are not usually processed by the NER pathway are nonetheless repaired more efficiently in the transcribed strands of active genes (14,24). In the latter situation other factors may play a role in targeting various DNA repair modes to sites of damage in the transcribed strand of active genes.…”

The role of Cockayne Syndrome group B (CSB) protein in base excision repair and aging

“…Importantly, after exposure to IR, CSB deficient transformed fibroblasts, mouse embryonic fibroblasts (MEF), embryonic stem (ES) cells and keratinocytes from CSB knockout mice all show a marked reduction in survival (de Waard et al, 2004;de Waard et al, 2003;Leadon and Cooper, 1993;Tuo et al, 2001). While IR induces a variety of DNA lesions including single stranded DNA breaks (SSBs), double-strand DNA breaks (DSBs) and oxidative base damage, the observed hypersensitivity has been ascribed to oxidative DNA modifications (de Waard et al, 2004;de Waard et al, 2003), which normally are repaired by BER.…”

Urinary Bladder Lesions after the Chernobyl Accident: Immunohistochemical Assessment of p53, Proliferating Cell Nuclear Antigen, Cyclin D1 and p21WAF1/Cip1

“…13,32) Growth arrest after irradiation is thought to provide cells with additional time to repair DNA damage in late G1, G2 and possibly also S-phase.…”

“…32) It has been shown that wild-type p53 plays an essential role in transcription-coupled repair of DNA damage induced by oxidative stress, ionizing radiation and some chemical carcinogens. 35) The weak staining of p53-positive nuclei of bladder urothelium in both radiocontaminated groups likely represents wild-type p53 accumulation in response to DNA damage.…”