damage could impair the normal functions of the DNA and may even result in triggering a program of cell death (apoptosis). The children with this disease do not repair the active genes where oxidative damage occurs. Normally, oxidative damage repair is faster in the active genes (which make up less than five percent of the genome) than in inactive regions of the DNA. The resulting accumulation of oxidative damage could impair the normal functions of the DNA and may even result in triggering a program of cell death (apoptosis). Genetics Cockayne syndrome is classified genetically as follows: Mutations in the ERCC8 (also known as CSA) gene or the ERCC6 (also known as CSB) gene are the cause of Cockayne syndrome. Mutations in the ERCC6 gene mutation makes up ~70% of cases. The proteins made by these genes are involved in repairing damaged DNA via the transcription-coupled repair mechanism, particularly the DNA in active genes. DNA damage is caused by ultraviolet rays from sunlight, radiation, or free radicals in the body. A normal cell can repair DNA damage before it accumulates. If either the ERCC6 or the ERCC8 gene is altered (as in Cockayne Syndrome), DNA damage encountered during transcription isn't repaired, causing RNA polymerase to stall at that location, interfering with gene expression. As the unrepaired DNA damage accumulates, progressively more active gene expression is impeded, leading to malfunctioning cells or cell death, which likely contributes to the signs of Cockayne Syndrome such as premature aging and neuronal hypomyelination. Mechanism In contrast to cells with normal repair capability, CSA and CSB deficient cells are unable to preferentially repair cyclobutane pyrimidine dimers induced by the action of ultraviolet (UV) light on the template strand of actively transcribed genes. This deficiency reflects the loss of ability to perform the DNA repair process known as transcription coupled nucleotide excision repair (TC-NER). Within the damaged cell, the CSA protein normally localizes to sites of DNA damage, particularly inter-strand cross-links, double-strand breaks and some monoadducts. CSB protein is also normally recruited to DNA damaged sites, and its recruitment is most rapid and robust as follows: interstrand crosslinks > double-strand breaks > monoadducts > oxidative damage. CSB protein forms a complex with another DNA repair protein, SNM1A (DCLRE1A), a 5' – 3' exonuclease, that localizes to inter-strand cross-links in a transcription dependent manner. The accumulation of CSB protein at sites of DNA double-strand breaks occurs in