The many faces of Cockayne syndrome.

Abstract

The challenges intrinsic to the maintenance of genetic information are revealed when one surveys the growing list of human disorders caused by defects in the repair of damage to DNA. Although these diseases are extremely rare, their effects are often devastating for patients and their families. One such rare autosomal disease, Cockayne syndrome (CS), can be caused by mutations in two genes, CKN1 and ERCC6 , located on chromosomes 5 and 10, respectively. There are two complementation groups of CS: CS-A patients have mutations in CKN1 , whereas CS-B is caused by mutations in ERCC6 (also known as CSB ). In this issue of PNAS, Horibata et al . (1) describe a mutation in the ERCC6/CSB gene that gives rise to a different sun-sensitive, DNA-repair-deficient disease, UV-sensitive syndrome (UVsS). UV-sensitive syndrome comprises at least two complementation groups. Repair of photoproducts and many other “bulky” DNA lesions is carried out by the nucleotide excision repair (NER) pathway (2). NER of certain lesions has two operational modes: a general mechanism that operates throughout the genome, termed global genomic NER (GG-NER), and a distinct mode, transcription-coupled NER (TC-NER), which requires a subset of NER proteins plus additional factors and is targeted to transcriptionally active regions of the genome. Another pathway, base excision repair, operates on damage to bases induced by reactive oxygen species, ionizing radiation, and most alkylating agents. Xeroderma pigmentosum (XP) is the most prevalent human DNA repair deficient syndrome, with nearly 1,000 patients worldwide. There are seven complementation groups of XP with deficiencies in NER, named XP-A through XP-G; patients in the eighth group, XP variant, have normal NER but are deficient in translesion synthesis of DNA containing certain lesions. XP is characterized by sun sensitivity, abnormal skin pigmentation, a 1,000-fold increase in cancer in sun-exposed tissues, and progressive neurological …