Defective Transcription-Coupled Repair in Cockayne Syndrome B Mice Is Associated with Skin Cancer Predisposition

Abstract

A mouse model for the nucleotide excision repair disorder Cockayne syndrome (CS) was generated by mimicking a truncation in the CSB(ERCC6) gene of a CS-B patient. CSB-deficient mice exhibit all of the CS repair characteristics: ultraviolet (UV) sensitivity, inactivation of transcription-coupled repair, unaffected global genome repair, and inability to resume RNA synthesis after UV exposure. Other CS features thought to involve the functioning of basal transcription/repair factor TFIIH, such as growth failure and neurologic dysfunction, are present in mild form. In contrast to the human syndrome, CSB-deficient mice show increased susceptibility to skin cancer. Our results demonstrate that transcription-coupled repair of UV-induced cyclobutane pyrimidine dimers contributes to the prevention of carcinogenesis in mice. Further, they suggest that the lack of cancer predisposition in CS patients is attributable to a global genome repair process that in humans is more effective than in rodents.

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

“…Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. disrupted in the CSB gene (also called ERCC6) have increased susceptibility to skin cancer (van der Horst et al, 1997). The life expectancy of patients with CS is approximately 12 years (for extensive reviews on clinical characteristics of CS see (Nance and Berry, 1992) and (Licht et al, 2003).…”

How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

“…In humans, defects in the Cockayne syndrome (CS) A or B genes result in a transcriptional coupled NER defect, and these individuals exhibit growth failure, progressive neurological defects, along with kyphosis, osteoporosis, and a dramatically reduced mean life span of 12.5 years (Cleaver, 2005;Nance and Berry, 1992). Mice mutant for CS-B show some phenotypes of the human syndrome (van der Horst et al, 1997), but when crossed to NER-deficient Xpa-/-mice, the NER defect is complete and defective phenotypes are exacerbated, resembling those of the Ercc1-/-mice (van der Pluijm et al, 2007). The Csb m/m /Xpa-/-mice were growth retarded, exhibited multiple tissue defects, and had progeroid phenotypes, ultimately dying by 22 days of age.…”

Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

“…The neurodegenerative symptoms in mice are generally milder than in human and the cancer burden higher, especially for Cs (van der Horst et al, 1997;van der Horst et al, 2002;Laposa et al, 2007b) and Xpa De Vries, 1997;Tanaka et al, 2001). Variations due to strain backgrounds are also factors, especially regarding life-shortening versus cancer risk (Li et al, 2007;Partridge and Gems, 2007).…”

“…Variations due to strain backgrounds are also factors, especially regarding life-shortening versus cancer risk (Li et al, 2007;Partridge and Gems, 2007). The Cs-b strain that has been most extensively used (van der Horst et al, 1997;Laposa et al, 2007b) contains a truncation mutation that may resemble the mild human UV-sensitive disorder associated with an early truncation in CSB that lacks neurodegeneration (Horibata et al, 2004), unlike most CSB patients with amino acid changes and termination mutations scattered throughout the gene. There is consequently a need for further mouse models especially those that recapitulate the mutations causing severe CS clinical disorders.…”