Werner syndrome protein suppresses the formation of large deletions during the replication of human telomeric sequences

Werner syndrome (WS) is a disorder characterized by features of premature aging and increased cancer that is caused by loss of the RecQ helicase WRN. Telomeres consisting of duplex TTAGGG repeats in humans protect chromosome ends and sustain cellular proliferation. WRN prevents the loss of telomeres...

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Veröffentlicht in:Cell cycle (Georgetown, Tex.) Tex.), 2012-08, Vol.11 (16), p.3036-3044
Hauptverfasser: Damerla, Rama Rao, Knickelbein, Kelly E., Strutt, Steven, Liu, Fu-Jun, Wang, Hong, Opresko, Patricia L.
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container_issue 16
container_start_page 3036
container_title Cell cycle (Georgetown, Tex.)
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creator Damerla, Rama Rao
Knickelbein, Kelly E.
Strutt, Steven
Liu, Fu-Jun
Wang, Hong
Opresko, Patricia L.
description Werner syndrome (WS) is a disorder characterized by features of premature aging and increased cancer that is caused by loss of the RecQ helicase WRN. Telomeres consisting of duplex TTAGGG repeats in humans protect chromosome ends and sustain cellular proliferation. WRN prevents the loss of telomeres replicated from the G-rich strand, which can form secondary G-quadruplex (G4) structures. Here, we dissected WRN roles in the replication of telomeric sequences by examining factors inherent to telomeric repeats, such as G4 DNA, independently from other factors at chromosome ends that can also impede replication. For this we used the supF shuttle vector (SV) mutagenesis assay. We demonstrate that SVs with [TTAGGG] 6 sequences are stably replicated in human cells, and that the repeats suppress the frequency of large deletions despite G4 folding potential. WRN depletion increased the supF mutant frequency for both the telomeric and non-telomeric SVs, compared with the control cells, but this increase was much greater (27-fold) for telomeric SVs. The higher SV mutant frequencies in WRN-deficient cells were primarily due to an increase in large sequence deletions and rearrangements. However, WRN depletion caused a more dramatic increase in deletions and rearrangements arising within the telomeric SV (70-fold), compared with non-telomeric SV (8-fold). Our results indicate that WRN prevents large deletions and rearrangements during replication, and that this role is particularly important in templates with telomeric sequence. This provides a possible explanation for increased telomere loss in WS cells.
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The higher SV mutant frequencies in WRN-deficient cells were primarily due to an increase in large sequence deletions and rearrangements. However, WRN depletion caused a more dramatic increase in deletions and rearrangements arising within the telomeric SV (70-fold), compared with non-telomeric SV (8-fold). Our results indicate that WRN prevents large deletions and rearrangements during replication, and that this role is particularly important in templates with telomeric sequence. 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The higher SV mutant frequencies in WRN-deficient cells were primarily due to an increase in large sequence deletions and rearrangements. However, WRN depletion caused a more dramatic increase in deletions and rearrangements arising within the telomeric SV (70-fold), compared with non-telomeric SV (8-fold). Our results indicate that WRN prevents large deletions and rearrangements during replication, and that this role is particularly important in templates with telomeric sequence. This provides a possible explanation for increased telomere loss in WS cells.</abstract><cop>United States</cop><pub>Taylor &amp; Francis</pub><pmid>22871734</pmid><doi>10.4161/cc.21399</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central
subjects Base Sequence
Binding
Biology
Bioscience
Calcium
Cancer
Cell
Cell Line, Tumor
Cycle
DNA Replication
Exodeoxyribonucleases - genetics
Exodeoxyribonucleases - metabolism
G-quadruplex
G-Quadruplexes
Gene Rearrangement
Genes, Reporter
Genes, Suppressor
Genetic Vectors - genetics
Genetic Vectors - metabolism
Humans
Landes
Molecular Sequence Data
Mutagenesis
Organogenesis
Proteins
RecQ Helicases - genetics
RecQ Helicases - metabolism
Repetitive Sequences, Nucleic Acid
RNA, Transfer - genetics
RNA, Transfer - metabolism
Sequence Deletion
telomere
Telomere - genetics
Telomere - metabolism
Werner Syndrome - enzymology
Werner Syndrome - genetics
Werner Syndrome Helicase
WRN helicase
title Werner syndrome protein suppresses the formation of large deletions during the replication of human telomeric sequences
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