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UV-sensitive syndrome (UV SS) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma. Despite mild clinical features, cells from individuals with UV SS, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER), which removes DNA damage in actively transcribed genes. Three of the seven known UV SS cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively). The remaining four individuals with UV SS, one of whom is described for the first time here, formed a separate UV SS-A complementation group; however, the responsible gene was unknown. Using exome sequencing, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UV SS-A. The UVSSA protein interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites. Our findings provide mechanistic insights into the processing of stalled RNA polymerase and explain the different clinical features across these TC-NERg-deficient disorders., Nature Genetics, 44(5), pp.586-592; 2012

To determine whether DNA polymerase plays a role in the hypermutation of immunoglobulin variable genes, we examined the frequency and pattern of substitutions in variable VH6 genes from the peripheral blood lymphocytes of three patients with xeroderma pigmentosum variant disease, whose polymerase had genetic defects. The frequency of mutation was normal but the types of base changes were different: there was a decrease in mutations at A and T and a concomitant rise in mutations at G and C. We propose that more than one polymerase contributes to hypermutation and that if one is absent, others compensate. The data indicate that polymerase is involved in generating errors that occur predominantly at A and T and that another polymerase(s) may preferentially generate errors opposite G and C.

DNA polymerase kappa (pol kappa) is a member of the Y-family of DNA polymerases that are thought to function in translesion synthesis (TLS) past different types of DNA damage. Here, we show that pol kappa-deficient mouse cells have substantially reduced (but not absent) levels of nucleotide excision repair (NER) of UV damage, as measured by several methods. Our results provide evidence for an unexpected role for pol kappa in mammalian NER.

Mutants able to grow in the presence of 1.2 mg/ml streptomycin were isolated from Escherichia coli WP2 after exposure to ultraviolet light (UV) or in the absence of any treatment (spontaneous), and from a umuC derivative after exposure to UV and delayed photoreversal. These mutants, characterized as streptomycin resistant (Smr) or dependent (Sud), carry mutations in the rpsL gene. This gene was amplified using the polymerase chain reaction and sequenced. Mutations induced by UV were largely (76%) of the Smr phenotype, all of which were changes at an A: T base pair at codons 42 or 87. Mutations induced by UV plus delayed photoreversal in the non-UV-mutable umuC122 derivative of WP2 were exclusively of the Smd phenotype and all occurred at G: C base pairs at codons 41, 90 or 91. These results are consistent with current understanding of the mechanism of mutagenesis by UV and delayed photoreversal. A broader spectrum of mutations was seen in the spontaneous series including three-base deletions leading to amino acid loss (2 of codon 93, 1 of codon 87). Of particular note was the number of intragenic second site mutations in the spontaneous series, most if not all of which appeared to be silent with respect to streptomycin phenotype. It is necessary to postulate a high rate of formation of such mutations at some stage during the experiment. One possibility is that spontaneous mutation may often occur in bursts when an error correction mechanism (eg., proofreading, mismatch correction) is temporarily inactive. In all, 12 different mutations conferring the ability to grow in the presence of streptomycin were identified, five Smr and seven Smd, including two three-base deletions. The mutations fall into two small regions of the gene, one spanning codons 40–43, the other 87–93. Both Smr and Smd mutations were found in each region. The sequence of the wild-type rpsL gene of E. coli WP2 (a B/r strain) was identical to that of E. coli K12, in contrast to the situation with a number of other genes. The sequence conservation may be a consequence of codon usage bias in this highly expressed gene.

Ten DNA repair (rad) genes from the fission yeast, Schizosaccharomyces pombe were mapped to the 17 NotI fragments of the three chromosomes. Nine of the genes map to chromosome I, but there is no evidence for significant clustering.

Nature 465, 1044–1048 (2010) It was brought to our attention by D. Guillaume (Chimie Therapeutique, CNRS) that deoxyribose C4′ of the cyclobutane pyrimidine dimer (CPD) photoproduct in the TT2 structure (Protein Data Bank accession number PDB 3MR4) has an inverted configuration. After further refinement, we obtained the correct sugar configuration (see Fig.

ATAXIA telangiectasia (AT) is an autosomal recessive defect in man showing among the clinical features1 : cerebellar ataxia, telangiectasia, IgA deficiency, an enhanced frequency of malignancy and an enhanced level of spontaneous chromosome instability2. There have also been reports of increased sensitivity to X rays after radiotherapy3–5 and increased chromosome aberrations induced by ionising radiation in leukocyte cultures from AT patients6,7. We report here cell survival experiments which indicate that the clinically observed enhanced sensitivity of AT patients to ionising radiation is manifest at the cellular level.

UV-A: Biological Effects of Ultraviolet Radiation, with Emphasis on Human Responses to Longwave Ultraviolet. By J. A. Parrish, R. A. Anderson, F. Urbach and D. Pitts. Pp.262. (Plenum: New York and London, 1978.) £15.75.