title: The Werner's Syndrome RecQ helicase/exonuclease at the nexus of cancer and aging.
abstract: Werner's Syndrome (WS) or adult-onset progeria is an autosomal recessive disorder of accelerated aging caused by mutations of the DNA RecQ helicase/exonuclease (WRN). WRN is an ATP-dependent helicase with 3' to 5' DNA exonuclease activity that regulates the replicative potential of dividing cells, and WRN loss-of-function mutations promote cellular senescence and neoplastic transformation. These molecular findings translate clinically into adult-onset progeria manifested by premature hair graying, dermal atrophy, cardiovascular disease, and cancer predilection along with a markedly reduced life expectancy. Recently, a patient with WS who developed pancreatic adenocarcinoma was identified in Honolulu suggesting a significant prevalence of loss-of-function WRN mutations in Hawaii's Japanese-American population. Based upon the indigenous Japanese WRN loss-of-function mutation heterozygote rate of 6 per 1,000, we speculate the possibility of approximately 1,200 heterozygotes in Hawaii. Our ongoing studies aim to evaluate Hawaii's true allelic prevalence of WRN loss-of-function mutations in the Japanese-American population, and the role of WRN silencing in sporadic cancers. In summary, WRN plays a nexus-like role in the complex interplay of cellular events that regulate aging, and analysis of WRN polymorphisms in Hawaii's population will generate novel insights to advance care for age-related pathologies.
authors.affiliation: Department of Surgery, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, USA. sgschun@hawaii.edu
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Chun
authors.forename: David S
authors.initials: DS
authors.lastname: Shaeffer
authors.forename: Peter K
authors.initials: PK
authors.lastname: Bryant-Greenwood
mesh_terms: D000328:Adult; D017668:Age of Onset; D000375:Aging / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D005090:Exodeoxyribonucleases / Q000235:genetics*; D005092:Exonucleases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006254:Hawaii / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D011110:Polymorphism, Genetic; D015995:Prevalence; D053484:RecQ Helicases / Q000235:genetics*; D018570:Risk Assessment; D014898:Werner Syndrome / Q000453:epidemiology / Q000235:genetics*; D000071657:Werner Syndrome Helicase
chemical_list: D005090:Exodeoxyribonucleases; D005092:Exonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase