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

[werner syndrome]

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 (G 4 ) structures . Here , we dissected WRN roles in the replication of telomeric sequences by examining factors inherent to telomeric repeats , such as G 4 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 G 4 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 .

Diseases
Validation

Diseases presenting "deficient cells" symptom

child syndrome

esophageal adenocarcinoma

gm1 gangliosidosis

junctional epidermolysis bullosa

kindler syndrome

lymphangioleiomyomatosis

neonatal adrenoleukodystrophy

werner syndrome

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