Cellular Responses to DNA Damage and Human Chromosome Instability Syndromes

Abstract

Ataxia telangiectasia (AT), Fanconi’s anemia (FA), Werner’s syndrome (WS), Bloom’s syndrome (BS), and Nijmegen breakage syndrome (NBS) are pleiotropic disorders that have occasionally been referred to as premature aging diseases. In part, this designation refers to the clinical observation that patients with these severe diseases show a variety of disorders that tend to accompany aging: skin changes, endocrine abnormalities, and higher relative risk and incidence of cancer. These disease have also been grouped together because cells from patients with AT, FA, WS, BS, and NBS have defects in maintaining genomic stability and integrity, even though patients with these syndromes have not been shown to carry germ-line p53 mutations like Li-Fraumeni patients (see Chapters 14 and 15). Further, cells from patients with any of these five syndromes have in common certain unique sensitivities to DNA damaging agents. However, the patients and their cells can be contrasted to xeroderma pigmentosum (XP), trichothiodistrophy, and Cockayne’s syndrome (CS) patients (Chapter 18) in that AT, FA, WS, BS, and NBS patients tend to show little, if any, sensitivity to UV radiation. In this chapter, we summarize some of the clinical presentations of the human chromosome instability diseases, and discuss the molecular properties of the genes encoding AT, FA, WS, BS, and NBS.