Premium
Werner syndrome gene variants in human sarcomas
Author(s) -
Hsu Jessica J.,
KamathLoeb Ashwini S.,
Glick Eitan,
Wallden Brett,
Swisshelm Karen,
Rubin Brian P.,
Loeb Lawrence A.
Publication year - 2010
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20586
Subject(s) - biology , exonuclease , helicase , werner syndrome , genetics , gene , premature aging , microbiology and biotechnology , genome instability , nonsynonymous substitution , dna , genome , dna polymerase , dna damage , rna
Abstract Werner syndrome is an autosomal inherited disease that is characterized by premature aging. The gene mutated in Werner syndrome (WS), WRN , encodes both a 3′ → 5′ DNA helicase and a 3′ → 5′ DNA exonuclease. Among the WS phenotypes is an exceptionally high incidence of sarcomas. We asked whether spontaneous sarcomas, not known to be associated with WS, also harbor mutations or unreported single nucleotide polymorphisms (SNPs) in WRN . We analyzed RNA or DNA sequences within the helicase and exonuclease domains from 51 and 69 matched sarcoma and adjacent normal tissues, respectively. Among a total of 13 nucleotide variants detected, we identified three novel nonsynonymous substitutions: c.611C>T, c.809_810insT, and c.1882C>G. We further characterized one, c.611C>T, which results in substitution of an evolutionarily conserved proline at amino acid 204 in the exonuclease domain with leucine. We show that P204L WRN exhibits a reduction of WRN exonuclease activity; the specific activity is ∼10‐fold lower than that of wild‐type WRN. In contrast, the helicase activity of P204L WRN is reduced less than twofold. © 2009 Wiley‐Liss, Inc.