Mammalian RAD23 homologs: multifunctional. proteins in DNA repair and development

Preservation of an intact genome is of utmost importance to all living organisms. However. the integrity of DNA. the carrier of genetic information required for proper functioning of cellular processes. is continuously challenged. Cells must overcome endogenous (metabolic) and exogenous (environmental) threats, as well as the intrinsic instability of chemical bonds in DNA itself (e.g. deamination and depurination). Oxidative stress. ultraviolet (UV) light. ionizing radiation (X-rays). and numerous chemicals induce a wide variety of lesions in the DNA. DNA damage can affect cellular processes and can have severe consequences for human health. Its direct effect at the cellular level is inhibition of vital processes like transcription and replication resulting in cell cycle arrest. Accumulation of lesions in DNA above certain thresholds can lead either to (programmed) cell death by apoptosis or to permanent alterations in the genetic code (mutations). These mutations can in turn cause changes in metabolic processes. inborn defects or overall functional decline contributing to premature aging. Mutations. specifically in proto-oncogenes and tUITIor suppressor genes. are directly responsible for tUITIor initiation and subsequent progression of the multistep process of carcinogenesis. To guard the vital genetic information and prevent the harmful consequences of DNA damage. an intricate network of genome caretaking systems has evolved (schematically depicted in Figure 1). Multiple DNA repair processes and cell cycle control mechanisms constitute an important component of this genome protection network. For a comprehensive review of DNA damage and the intricate network of DNA repair systems in general. the interested reader is referred to Friedberg, Walker, and Siede (1995) and Hoeijmakers (2001).