Which of the following is DNA repair defect
Xeroderma Pigmentosum Patients with another inherited disorder, xeroderma pig- mentosum, are at increased risk for the development of cancers of sun-exposed skin. The basis for this disorder is defective DNA repair. Ultraviolet (UV) rays in sunlight cause cross-linking of pyrimidine residues, preventing normal DNA replication. Such DNA damage is repaired by the nucleotide excision repair system. Several proteins are involved in nucleotide excision repair, and an inherited loss of any one of these can give rise to xeroderma pigmentosum. Diseases with Defects in DNA Repair by Homologous Recombination A group of autosomal recessive disorders comprising Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia is characterized by hypersensitivity to other DNA- damaging agents, such as ionizing radiation (in Bloom syn- drome and ataxia-telangiectasia), or to DNA cross-linking agents, such as nitrogen mustard (in Fanconi anemia). Their phenotype is complex and includes, in addition to predisposition to cancer, features such as neural symptoms (in ataxia-telangiectasia), anemia (in Fanconi anemia), and developmental defects (in Bloom syndrome). The gene mutated in ataxia-telangiectasia is ATM, which encodes a protein kinase that is impoant in recognizing DNA damage caused by ionizing radiation and initiating p53 activation. Evidence for the role of DNA repair genes in the origin of cancer also comes from the study of hereditary breast cancer. Mutations in two genes, BRCA1 and BRCA2, account for 50% of cases of familial breast cancer. In addi- tion to breast cancer, women with BRCA1 mutations have a substantially higher risk of epithelial ovarian cancers, and men have a slightly higher risk of prostate cancer. Like- wise, mutations in the BRCA2 gene increase the risk of breast cancer in both men and women, as well as cancer of the ovary, prostate, pancreas, bile ducts, stomach, melano- cytes, and B lymphocytes. Although the functions of these genes have not been elucidated fully, cells that lack these genes develop chromosomal breaks and severe aneuploidy. Indeed, both genes seem to function, at least in pa, in the homologous recombination DNA repair pathway. For example, BRCA1 forms a complex with other proteins in the homologous recombination pathway and also is linked to the ATM kinase pathway. BRCA2 was identified as one of several genes mutated in Fanconi anemia, and the BRCA2 protein has been shown to bind to RAD51, a protein required for homologous recombination. Similar to other tumor suppressor genes, both copies of BRCA1 and BRCA2 must be inactivated for cancer to develop. Although linkage of BRCA1 and BRCA2 to familial breast cancers is estab- lished, these genes are rarely inactivated in sporadic cases of breast cancer. In this regard, BRCA1 and BRCA2 are dif- ferent from other tumor suppressor genes, such as APC and TP53, which are inactivated in both familial and spo- radic cancers. ref Robbins 8/e p275; 9/e p314
Retinoblastoma
Neurofibromatosis
Xeroderma pigmentosum
MEN1
General anatomy