Abstract
Telomeric abnormalities caused by loss of function of the RecQ helicase WRN are linked to the multiple premature ageing phenotypes that characterize Werner syndrome. Here we examine WRN's role in telomeric maintenance, by comparing its action on a variety of DNA structures without or with telomeric sequences. Our results show that WRN clearly prefers to act on strand invasion intermediates in a manner that favours strand invasion and exchange. Moreover, WRN unwinding of these recombination structures is further enhanced when the invading strand contains at least three G-rich single-stranded telomeric repeats. These selectivities are most pronounced at NaCl concentrations within the reported intranuclear monovalent cation concentration range, and are partly conferred by WRN's C-terminal region. Importantly, WRN's specificity for the G-rich telomeric sequence within this precise structural context is particularly relevant to telomere metabolism and strongly suggests a physiological role in telomeric recombination processes, including T-loop dynamics.
Highlights
Telomeric abnormalities caused by loss of function of the RecQ helicase WRN are linked to the multiple premature ageing phenotypes that characterize Werner syndrome
Since intranuclear monovalent cation concentration is reported to be as high as 250 mM, effects of NaCl concentration were examined here and in many subsequent experiments addressing WRN’s DNA structure and sequence preferences
Adenosine triphosphate (ATP)-dependent WRN unwinding on these substrates was revealed by appearance of faster-migrating products after native polyacrylamide gel electrophoresis (PAGE) (Fig. 1b)
Summary
Telomeric abnormalities caused by loss of function of the RecQ helicase WRN are linked to the multiple premature ageing phenotypes that characterize Werner syndrome. WRN’s specificity for the G-rich telomeric sequence within this precise structural context is relevant to telomere metabolism and strongly suggests a physiological role in telomeric recombination processes, including T-loop dynamics. Several human diseases are associated with telomere instability including Werner syndrome (WS), an autosomal recessive disorder characterized by premature emergence of numerous ageing phenotypes that include cataracts, atherosclerosis and increased cancer susceptibility[14,15,16] These multiple ageing features result from defects in a single gene product, WRN17. Our results demonstrate that WRN preferentially acts on these recombination intermediates and with a directionality promoting further strand invasion This activity is further enhanced by the presence of singlestranded, unstructured G-rich telomeric sequence along the invading strand, a structural context precisely relevant to telomeric HR and T-loop dynamics. Our results strongly suggest that WRN acts in telomeric HR processes possibly including T-loop formation
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