Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome

Abstract

UV-sensitive syndrome (UV s S) is a rare autosomal recessive disorder characterized by photosensitivity and mild freckling but without neurological abnormalities or skin tumors. UV s S cells show UV hypersensitivity and defective transcription-coupled DNA repair of UV damage. It was suggested that UV s S does not belong to any complementation groups of known photosensitive disorders such as xeroderma pigmentosum and Cockayne syndrome (CS). To identify the gene responsible for UV s S, we performed a microcellmediated chromosome transfer based on the functional complementation of UV hypersensitivity. We found that one of the UV s S cell lines, UV s 1KO, acquired UV resistance when human chromosome 10 was transferred. Because the gene responsible for CS group B (CSB), which involves neurological abnormalities and photosensitivity as well as a defect in transcription-coupled DNA repair of UV damage, is located on chromosome 10, we sequenced the CSB gene from UV s 1KO and detected a homozygous null mutation. Our results indicate that previous complementation analysis of UV s 1KO was erroneous. This finding was surprising because a null mutation of the CSB gene would be expected to result in CS features such as severe developmental and neurological abnormalities. On the other hand, no mutation in the CSB cDNA and a normal amount of CSB protein was detected in Kps3, a UV s S cell line obtained from an unrelated patient, indicating genetic heterogeneity in UV s S. Possible explanations for the discrepancy in the genotype-phenotype relationship in UV s 1KO are presented. N ucleotide excision repair (NER) is a versatile DNA repair system that removes a wide range of DNA lesions including UV-induced lesions (1). There are two subpathways in NER. One is transcription-coupled DNA repair (TCR), which preferentially removes DNA damage that blocks ongoing transcription in the transcribed DNA strand of active genes, and the other is global genome repair (GGR), which removes lesions throughout the genome including those from the nontranscribed strand in the active gene (2). There are several NER-deficient disorders, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), cerebro-oculo-facio-skeletal syndrome, trichothiodystrophy, and UV-sensitive syndrome (UV s S). Hypersensitivity to sunlight is a common hallmark of these rare, autosomal recessive diseases that otherwise are highly heterogeneous with respect to additional features and genetic background. XP patients exhibit a Ͼ1,000-fold increased incidence of sun-induced skin cancer and often experience accelerated neurodegeneration. XP is classified into seven genetic complementation groups (XP-A to XP-G) and a variant form (XP-V) (1). XP-A to XP-G have a defect in TCR and GGR, except for XP-C and XP-E (2), which have a defect in GGR only. XP-V has a normal NER but a defect in translesion DNA synthesis (3). CS is characterized by an abnormality in physical and neurological development with dysmyelination but no predisposition to skin cancer (4). CS is classified into two g...

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

“…The severity of the disease does not seem to correlate with the site or nature of the CSB mutation, suggesting that the genetic background and/or environmental factors or downstream targets of a CSB protein-dependent regulation may be involved in determining the specific pathological phenotype of CS (Colella et al, 1999;Mallery et al, 1998). A report from Tanaka and coworkers (Horibata et al, 2004), which describes a patient suffering from UV-sensitivity Syndrome, shows that complete absence of the CSB gene product can give rise to UV-sensitivity but not Cockayne Syndrome. This suggests that presence of truncated or non-functional CSB gene products may prevent the completion of (a) certain process(es).…”

Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair

“…ERCC8 and ERCC6 genes are responsible for both CS and UV S S 7,8 . To evaluate whether UVSSA mutations may also result in CS-phenotypes, we sequenced the UVSSA gene of 61 CS-patients whose genetic defects had not yet been determined (Supplementary Table 4).…”

Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair

“…CS would also resemble an acceleration of normal aging, in which the brain accumulates oxidative damage (Lu et al, 2004). Recently a complete absence of CSB protein was found in a very mildly photosensitive patient, implying that mutant CSB proteins in other patients could be the cause of more severe disease (Horibata et al, 2004). This is reminiscent of other neurodegenerative diseases in which the mutant proteins are toxic and their loss can relieve some neurodegenerative symptoms (Arrasate et al, 2004;Harper et al, 2005;Santacruz et al, 2005).…”