BLM and SLX4 play opposing roles in recombination‐dependent replication at human telomeres. (6th September 2017)

• Record Type: Journal Article
• Authors: Sobinoff, Alexander P; Allen, Joshua AM; Neumann, Axel A; Yang, Sile F; Walsh, Monica E; Henson, Jeremy D; Reddel, Roger R; Pickett, Hilda A
• Is Part Of: EMBO journal. Volume 36:Number 19(2017)
• Page Start: 2907
• Page End: 2919
• Publication Date: 2017-09-06
• Subjects: ALT -- BLM -- SLX4 -- telomere recombination -- telomere synthesis; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201796889
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Alternative lengthening of telomeres (ALT) is a telomere lengthening pathway that predominates in aggressive tumors of mesenchymal origin; however, the underlying mechanism of telomere synthesis is not fully understood. Here, we show that the BLM–TOP3A–RMI (BTR) dissolvase complex is required for ALT‐mediated telomere synthesis. We propose that recombination intermediates formed during strand invasion are processed by the BTR complex, initiating rapid and extensive POLD3‐dependent telomere synthesis followed by dissolution, with no overall exchange of telomeric DNA. This process is counteracted by the SLX4–SLX1–ERCC4 complex, which promotes resolution of the recombination intermediate, resulting in telomere exchange in the absence of telomere extension. Our data are consistent with ALT being a conservative DNA replication process, analogous to break‐induced replication, which is dependent on BTR and counteracted by SLX4 complex‐mediated resolution events. Synopsis: Recombination‐mediated alternative lengthening of telomeres (ALT) found in many tumor cells appears as a conservative DNA replication process, involving POLD3‐dependent telomere synthesis and BLM‐TOP3A‐mediated dissolution of recombination intermediates to prevent telomere exchange. BLM helicase expression promotes ALT‐mediated telomere synthesis, facilitating long‐tract telomere extension followed by telomeric dissolution. BLM function in complex with TOP3A and RMI (BTR) and requires POLD3 and RAD51 to promote ALT‐mediated telomere synthesis. Expression of SLX4 endonuclease represses ALT‐mediated telomere synthesis by promoting resolution of telomeric recombination intermediates after strand invasion. Telomere crossover events are strongly correlated with an absence of ALT‐mediated telomere extension. Abstract : Alternative lengthening of telomeres (ALT) appears as a conservative DNA replication process involving POLD3‐dependent telomeres synthesis and BLM‐TOP3A‐mediated prevention of telomere exchange.