Human Genetic Disorders Associated with Genome Instability, Premature Aging and Cancer Predisposition

Abstract

Our genetic material is constantly damaged by internal sources such as reactive oxygen species and external sources such as ionizing radiation and sunlight. However, we seldom notice these injuries because our cells possess elegant DNA surveillance networks that serve to maintain cellular homeostasis. These networks are complex signal transduction pathways that coordinate cell cycle checkpoints and DNA repair processes to eliminate DNA damage, as well as invoking pathways such as sustained growth arrest (i.e., accelerated senescence) and apoptotic cell death to eliminate injured cells from the proliferating population. The p53 tumor suppressor protein and its downstream effector p21 are key regulators of these various responses. Failure of cells to properly activate p53/p21-mediated events following genotoxic stress may lead to the development of genomic instability and the emergence of malignant cells which exhibit stem cell-like properties. It is therefore not surprising that defects in major players of the DNA surveillance networks are the underlying cause for numerous debilitating human genetic disorders that are characterized by genomic instability, premature aging, and cancer proneness. In this article, we first provide an update on the role of the p53 signaling pathway in determining the fate of human cells following exposure to DNA-damaging agents. We next review the clinical and laboratory features of the most extensively studied human genome instability disorders including xeroderma pigmentosum, Cockayne syndrome, ataxia telangiectasia, and Li-Fraumeni syndrome, and discuss the current knowledge on the biological consequences of deregulated p53 signaling in cells derived from patients with such disorders.

Reappraisal of the Concept of Accelerated Aging in Neurodegeneration and Beyond

“…In particular, the phenotypes of genome instability disorders that result from autosomal recessive mutations are associated with ineffective genome maintenance systems, deficiencies in DNA helicase activity or an aberrant nuclear architecture. Three groups of these disorders include the sunlight hypersensitivity disorders: Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy; the ionizing radiation hypersensitivity disorders including Ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS); and the progeroid disorders including Werner syndrome, Hutchinson-Gilford progeria syndrome, Bloom syndrome, Rothmund-Thompson syndrome and Fanconi anemia [277][278][279].…”