Abstract. Cockayne syndrome (CS) and xeroderma pigmentosum (XP) are human photosensitive diseases with mutations in the nucleotide excision repair (NER) pathway, which repairs DNA damage from UV exposure.
Cockayne syndrome (CS) is a rare recessive genetic disease characterized in part by premature ageing and photosensitive skin. Because of the latter characteristic, this syndrome was considered to be an example of a UV-sensitive DNA repair-defective human disorder.
Cockayne syndrome is an autosomal recessive genetic disorder. In about two-thirds of cases, it is due to the mutation of the ERCC6 gene, ERCC6 (10q11) conditions the production of a protein called CSB (for Cockayne syndrome B).
A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair. DNA repair defects can cause an accelerated aging disease or an increased risk of cancer, or sometimes both.
Nucleotide excision repair (NER) is the main pathway used by mammals to remove bulky DNA lesions such as those formed by UV light, environmental mutagens, and some cancer chemotherapeutic adducts from DNA. Deficiencies in NER are associated with the extremely skin cancer-prone inherited disorder xeroderma pigmentosum.
Cockayne syndrome (CS) and xeroderma pigmentosum (XP) are photosensitive diseases with mutations in the nucleotide excision repair (NER) pathway. XP patients have a very high incidence of UV-induced skin cancer, but CS patients have never been reported to develop cancer.
Mismatch repair (MMR) deficient cells usually have many DNA mutations, which may lead to cancer. MMR deficiency is most common in colorectal cancer, other types of gastrointestinal cancer, and endometrial cancer, but it may also be found in cancers of the breast, prostate, bladder, and thyroid.
At least five major DNA repair pathways—base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR) and non-homologous end joining (NHEJ)—are active throughout different stages of the cell cycle, allowing the cells to repair the DNA damage.
There are three types of repair mechanisms: direct reversal of the damage, excision repair, and postreplication repair. Direct reversal repair is specific to the damage. For example, in a process called photoreactivation, pyrimidine bases fused by UV light are separated by DNA photolyase (a light-driven enzyme).
There are two main mechanisms for repairing double strand breaks: homologous recombination and classical nonhomologous end joining. Homologous recombination involves the exchange of nucleotide sequences to repair damaged bases on both strands of DNA through the utilization of a sister chromatid.
The Weber-Cockayne type of EBS is caused by a genetic mutation in the keratin intermediate filaments 5 and 14 in the basal layer of the epidermis. Increased mechanical stress, which often occurs when hyperhidrosis is present, then leads to blister formation. Historically, EBS has been difficult to treat.
Cockayne's syndrome type B (CSB) is caused by deficiency in a helicase member of the SW12/SNF2 family of ATPases. Several mutations in the CSB gene have been described on chromosome 10q11. Another class of patients with Cockayne's syndrome shows concurrently clinical features of xeroderma pigmentosum (XP).
Two genes defective in Cockayne syndrome, CSA and CSB, have been identified so far. The CSA gene is found on chromosome 5. Both genes code for proteins that interacts with components of the transcriptional machinery and with DNA repair proteins.
CSB is a 168-kDa protein with 1493 amino acids. The N-terminal domain is followed by an acidic stretch, a glycine-rich region, a central helicase domain, two putative nuclear localization signal sequences, and a number of serine phosphorylation sites (Figure 1).
Human severe combined immune deficiency (SCID) is the most serious inherited immunological deficit. Recent work has revealed defects in the predominant pathway for double-strand break repair called nonhomologous DNA end joining, or NHEJ.
Cockayne syndrome is a rare disease which causes short stature, premature aging (progeria), severe photosensitivity, and moderate to severe learning delay. This syndrome also includes failure to thrive, very small head (microcephaly), and impaired nervous system development.
DNA direct reversal repair (DRR) is unique in that no DNA synthesis is required to correct the error and therefore repair via such mechanisms are error-free. In humans, DRR is carried out by two different pathways: the O6-methylguanine-DNA methyltransferase (MGMT) and the alkylated DNA repair protein B (AlkB) homologs.
Double-strand DNA breaks are common events in eukaryotic cells, and there are two major pathways for repairing them: homologous recombination and nonhomologous DNA end joining (NHEJ).
The DNA-mismatch repair system corrects base-base mismatches and small loops, whereas the nucleotide-excision repair system removes pyrimidine dimers and other helix-distorting lesions.
Base excision repair is a pathway that repairs replicating DNA throughout the cell cycle. Nucleotide excision repair is a pathway that repairs constantly damaging DNA due to UV rays, radiation and mutagens.
At least six genes—MSH2, MLH1, PMS2, MSH3, MSH6, and MLH3—are involved in mismatch repair.
It plays an important role in maintaining genomic stability and cellular homeostasis. For example, MMR increases the accuracy of DNA replication by 20–400-fold in Escherichia coli. The mismatch repair machinery distinguishes the newly synthesised strand from the template (parental) to begin the repair process.
DNA mismatch repair is a mechanism of repairing DNA by the removal of mismatched nucleotides via MMR proteins. The role of mismatch repair proteins in the prokaryotic DNA helped to study the mismatch repair system in the eukaryotic DNA as well.
Summary. Cockayne syndrome is a rare disease which causes short stature, premature aging (progeria), severe photosensitivity, and moderate to severe learning delay. This syndrome also includes failure to thrive in the newborn, very small head (microcephaly), and impaired nervous system development.