Human Premature Aging Disorders and Dysfunction of DNA Repair

Werner?s syndrome (WS) and Cockayne syndrome (CS) are rare human autosomal recessive disorders classified as segmental progeroid disorders. WS is marked by premature onset of age-related phenotypic changes (such as cataract and greying of hair etc) and genome instability. Cells derived from CS patients are defective in DNA repair, and CS patients display severe neurological abnormalities and certain features of premature aging. The accelerated aging features observed in these two genetically distinct syndromes make them ideal model systems to understand some of the basic mechanism(s) for aging process. WS is caused by mutations in the gene (wrn) encoding the Werner syndrome protein (WRN), a member of the RecQ family of DNA helicases with helicase and exonudease domains. Biochemical characterization of WRN enzymatic activities, identification of WRN interacting proteins and the cellular localization studies all suggest WRN?s participation in multiple DNA metabolic pathways for maintaining genomic integrity. CS arises from mutations in the CSA and CSB genes. While CSA belongs to ?WD? repeat containing protein family, CSB is a member of SNF2-like family with only a DNA stimulated ATPase activity. CSB is involved in different DNA transactions, notably transcription and DNA repair. Our recent understanding of the mechanism of action(s) of WRN and CSB proteins are expected to provide new insights into the aging process.