Abstract
Werner syndrome is a premature aging disease caused by loss of function mutations in the Werner syndrome protein (WRN) gene. WRN is a RecQ helicase that in contrast to every other member of this family of proteins possesses an exonuclease activity. The findings that cells lacking WRN activity display accelerated telomere shortening and WRN can be detected at chromosome ends suggest that this protein participates in some aspects of telomere metabolism. In this study we examined the impact of WRN on telomeric substrates with a 3' single-stranded overhang in vitro and show that WRN has sequence-specific exonuclease activity that removes several nucleotides inward with a periodical pattern from the 3' end of the telomeric overhang. This activity is strictly dependent on the presence of telomeric sequences in both the duplex DNA and 3' overhang DNA segment and is strongly inhibited by the telomeric factor POT1 but not TRF2. These data demonstrate that WRN processes telomeric DNA substrates with a 3' single-stranded overhang with high specificity and suggest that this protein could influence the configuration of telomere ends prior to the formation of a protective t-loop structure.
Highlights
Werner Syndrome (WS) is an autosomal recessive segmental aging disorder associated with a marked predisposition to cancer and vascular disease [1, 2]
In this study we investigated the biochemical properties of the Werner syndrome protein (WRN) protein at telomeres and describe in vitro studies that expose a unique property of WRN exonuclease on 3’ single-stranded overhang of telomeric DNA substrates mimicking natural telomere termini
We demonstrate that WRN exhibits sequence-specific exonuclease activity that removes, in a restricted fashion, several nucleotides inward from the G-rich 3’ single-stranded overhang of telomeric substrates
Summary
Werner Syndrome (WS) is an autosomal recessive segmental aging disorder associated with a marked predisposition to cancer and vascular disease [1, 2]. The first signs of this disorder appear after puberty and the disease is usually diagnosed in individuals 20 to 30 years of age. WS patients show increased predisposition to diseases observed during normal aging such as arteriosclerosis, osteoporosis, type II diabetes mellitus and a variety of tumors, primarily of mesenchymal origin [1, 3]. Myocardial infarction (MI) and cancer are the most common causes of death among WS patients, with a median age of death of approximately 47 years. WS is caused by mutations in the gene that encodes for the Werner syndrome protein (WRN), a protein that belongs to the class of enzymes termed RecQ helicases [4, 5]. WRN can unwind and/or hydrolyze a number of different DNA structures, from linear duplex DNA to single stranded regions of flap DNA substrates to synthetic replication forks and www.impactaging.com
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