Elsevier

DNA Repair

Volume 12, Issue 8, August 2013, Pages 656-671
DNA Repair

Blinded by the UV light: How the focus on transcription-coupled NER has distracted from understanding the mechanisms of Cockayne syndrome neurologic disease

https://doi.org/10.1016/j.dnarep.2013.04.018Get rights and content

Abstract

Cockayne syndrome (CS) is a devastating neurodevelopmental disorder, with growth abnormalities, progeriod features, and sun sensitivity. CS is typically considered to be a DNA repair disorder, since cells from CS patients have a defect in transcription-coupled nucleotide excision repair (TC-NER). However, cells from UV-sensitive syndrome patients also lack TC-NER, but these patients do not suffer from the neurologic and other abnormalities that CS patients do. Also, the neurologic abnormalities that affect CS patients (CS neurologic disease) are qualitatively different from those seen in NER-deficient XP patients. Therefore, the TC-NER defect explains the sun sensitive phenotype common to both CS and UVsS, but cannot explain CS neurologic disease. However, as CS neurologic disease is of much greater clinical significance than the sun sensitivity, there is a pressing need to understand its molecular basis. While there is evidence for defective repair of oxidative DNA damage and mitochondrial abnormalities in CS cells, here I propose that the defects in transcription by both RNA polymerases I and II that have been documented in CS cells provide a better explanation for many of the severe growth and neurodevelopmental defects in CS patients than defective DNA repair. The implications of these ideas for interpreting results from mouse models of CS, and for the development of treatments and therapies for CS patients are discussed.

Introduction

Patients with the genetic disease xeroderma pigmentosum (XP) are highly sensitive to sunlight exposure, and have a greater than 10,000× increased risk of cancer on sun exposed areas of the body [1]. Based upon the earlier discovery of nucleotide excision repair [2], the landmark observation by Cleaver [3] that patients with XP are unable to carry out nucleotide excision repair (NER) was the first description of a DNA repair disease. The subsequent discovery that cells from patients with Cockayne syndrome (CS) have a defect in a sub-pathway of NER, referred to as transcription-coupled nucleotide excision repair (TC-NER) [4], [5] led to the identification of CS as a DNA repair disease as well. CS is a rare neurodevelopmental disorder with progeriod features, and sun sensitivity, and the NER defect common to both diseases provided a convincing explanation for the shared sun sensitive phenotype.

The discovery of the TC-NER defect in CS cells brought this extremely rare disease to the attention of world-class scientists working on DNA repair and transcription, resulting in several ground breaking scientific publications, and much progress into understanding the mechanistic basis of TC-NER [6], [7]. In addition, knowledge of the DNA repair defect was essential to the cloning of the genes responsible for CS [8], [9]. However, the association between CS and TC-NER deficiency has had a negative impact as well. Numerous publications on the mechanistic basis of TC-NER, utilizing cells from CS patients, reinforced the association between CS and TC-NER deficiency. Furthermore, the shared NER deficiency in both XP and CS fostered the idea that all of the clinical features of CS, including the neurologic disease, are the result of the TC-NER defect (e.g. [10]). The obvious problem is that while both XP and CS patients have neurologic abnormalities, the nature of the neurologic abnormalities in CS are fundamentally different than those in XP [11], [12].

In my view, much of the confusion in the literature is the result of looking at CS through the lens of the well-known TC-NER deficiency. In fact, cells from CS patients have multiple abnormalities in addition to defective TC-NER. In this work, I will take the opposite approach, starting with a description of the clinical features of CS with a particular emphasis on CS neurologic disease. I then consider which of the various molecular abnormalities that have been described in CS cells, including but not limited to the TC-NER defect, provides the best explanation for the different pathologies of CS neurologic disease. Specifically, I will propose an updated version of the original transcription syndrome hypothesis of CS [13], [14], [15], [16] expanded to include an important role for defective transcription by both RNA polymerase I (RNAPI) and RNA polymerase II (RNAPII) in CS, and argue that this expanded transcription hypothesis provides a better explanation for many aspects of CS neurologic disease than defective DNA repair. I will also consider the implications of the expanded transcription syndrome hypothesis for interpreting recent findings from mouse models of CS. Finally, I will consider the translational implications of different hypotheses for the pathophysiology of CS. As such, this work is not intended to be a comprehensive review of CS, but a different way of looking at the mechanistic basis of CS neurologic disease. Since neurologic disease is of far greater clinical significance to CS patients than sun sensitivity, understanding its mechanistic basis has important implications for the development of treatments and therapies which are urgently needed.

Section snippets

Cockayne syndrome (CS) and CS neurologic disease

CS is a rare autosomal recessive disease, characterized by severe growth failure, neurologic disease, developmental abnormalities, degeneration of multiple organ systems including the eye and ear, cataracts, and, in most (but not all) patients, sun sensitivity [17], [18], [19], [20]. CS can result from mutations in either of two genes: ERCC6 (CSB) or ERCC8 (CSA). In addition, a subset of patients with mutations in the XPB, XPD, and XPG genes have the somatic features of CS, as well as the

Transcription-coupled NER and its relevance to CS

Before assessing the relevance of defective TC-NER for CS neurologic disease, it is necessary to provide some basic information about NER and TC-NER. Since several comprehensive and detailed reviews of various aspects of NER have been recently published in a special issue of DNA Repair [28] here I will give only a basic description of the processes, and refer interested readers to these reviews.

Defective repair of oxidative DNA damage in CS and its relationship to CS neurologic disease

The inability of defective TC-NER to explain the somatic features of CS does not rule out a possible role for defective repair of oxidative DNA damage in the CS phenotype. The concept that CS results from defective repair of oxidative DNA damage is a very popular concept in the literature, and has been reviewed by others [78], [79]. In my view, however, part of the attraction of the oxidative DNA damage hypothesis of CS is based in part on two mutually reinforcing but flawed concepts: CS as a

A New look at an old hypothesis: CS as a RNAPI and RNAPII transcription disease

The identification of the XPD and XPB helicases as components of the transcription factor TFIIH [102], [103] was an important discovery which dramatically impacted our understanding of the relationship between DNA repair, transcription, and human disease. This finding and subsequent work led to the concept that while XP is a DNA repair disorder, CS and trichothiodystrophy (TTD), could be thought of as “transcription syndromes”, i.e. diseases resulting from abnormalities of transcription [13],

An expanded version of the transcription syndrome hypothesis: CS as a RNA polymerase I and II transcription disorder

A combination of defective transcription by RNAPI, coupled with abnormalities in the regulation of transcription by RNAPII, provides plausible explanation for many of the somatic features of CS, including growth defects and aspects of CS neurologic disease. Some examples are given below, and a schematic diagram summarizing this hypothesis is given in Fig. 2. In Fig. 2 and the following text, I have separated the discussion of RNAPI and RNAPII for clarity, and to emphasize the potential role of

Mouse models of CS neurologic disease and their mechanistic interpretation

Several mouse models of CS have been generated, mostly from the Hoeijmakers laboratory, which have had an important impact on the CS field. The first of these was a mouse with a stop codon mutation in Csb [155]. While fibroblasts from these mice were sensitive to killing by UV light, and showed defects in measures of TC-NER, they had an increased incidence of skin cancer in response to UV, in contrast to human CS patients. These mice were slightly smaller than wild-type controls, and displayed

Therapeutic implications

Understanding the mechanistic basis of a human disease is essential for the rational development of treatments and therapies for the patients. At present, the only documented treatment for CS neurologic disease is for tremors and other motor complications that are observed in some CS type I patients [162]. For this reason, I have taken a critical look at multiple mechanisms of CS neurologic disease, because they have quite different implications for additional potential therapies.

As discussed

Summary and concluding remarks

CS is a devastating neurodevelopmental disorder, with growth abnormalities, progeriod features, and sun sensitivity. While it was the sun sensitivity that led to the discovery of the TC-NER defect in CS patients, sun sensitivity is a relatively trivial aspect of the clinical picture compared to the neurologic disease. As such, a better understanding of the mechanistic basis of CS neurologic disease is urgently needed, as it essential to the development of rational therapeutic strategies. In

Acknowledgements

This paper was inspired by meeting patients with CS, and discussions with their families, at events organized by the Share and Care Cockayne syndrome network (http://cockaynesyndrome.net/main/). I also thank Cheryl Marietta, Dr. Rebecca Laposa, and anonymous referees for suggestions and helpful comments on the manuscript, and Nicole Patten for the photomicrograph used in Fig. 1.

The human tissue used in Fig. 1 was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the

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      CSB is a multi-functional factor. Indeed, it has been implicated that CSB is not only involved in TC-NER and base excision repair, but also in mitochondrial function and regulation of transcription [12–15]. Despite the discovery of extremely delayed restart of RNA synthesis in cultured fibroblasts after irradiation with UV light as the diagnostic hallmark of CS, the importance of this feature to the development of CS neuropathology has long been questioned [12].

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